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1. Transcranial direct current stimulation of cerebellum alters spiking precision in cerebellar cortex: A modeling study of cellular responses

   https://doi.org/10.1371/journal.pcbi.1009609  

   Zhang, Xu ; Hancock, Roeland ; Santaniello, Sabato ( December 2021 , PLOS Computational Biology)

   Blackwell, Kim T. (Ed.)

   Transcranial direct current stimulation (tDCS) of the cerebellum has rapidly raised interest but the effects of tDCS on cerebellar neurons remain unclear. Assessing the cellular response to tDCS is challenging because of the uneven, highly stratified cytoarchitecture of the cerebellum, within which cellular morphologies, physiological properties, and function vary largely across several types of neurons. In this study, we combine MRI-based segmentation of the cerebellum and a finite element model of the tDCS-induced electric field (EF) inside the cerebellum to determine the field imposed on the cerebellar neurons throughout the region. We then pair the EF with multicompartment models of the Purkinje cell (PC), deep cerebellar neuron (DCN), and granule cell (GrC) and quantify the acute response of these neurons under various orientations, physiological conditions, and sequences of presynaptic stimuli. We show that cerebellar tDCS significantly modulates the postsynaptic spiking precision of the PC, which is expressed as a change in the spike count and timing in response to presynaptic stimuli. tDCS has modest effects, instead, on the PC tonic firing at rest and on the postsynaptic activity of DCN and GrC. In Purkinje cells, anodal tDCS shortens the repolarization phase following complex spikes (-14.7 ± 6.5% of baseline value, mean ± S.D.; max: -22.7%) and promotes burstiness with longer bursts compared to resting conditions. Cathodal tDCS, instead, promotes irregular spiking by enhancing somatic excitability and significantly prolongs the repolarization after complex spikes compared to baseline (+37.0 ± 28.9%, mean ± S.D.; max: +84.3%). tDCS-induced changes to the repolarization phase and firing pattern exceed 10% of the baseline values in Purkinje cells covering up to 20% of the cerebellar cortex, with the effects being distributed along the EF direction and concentrated in the area under the electrode over the cerebellum. Altogether, the acute effects of tDCS on cerebellum mainly focus on Purkinje cells and modulate the precision of the response to synaptic stimuli, thus having the largest impact when the cerebellar cortex is active. Since the spatiotemporal precision of the PC spiking is critical to learning and coordination, our results suggest cerebellar tDCS as a viable therapeutic option for disorders involving cerebellar hyperactivity such as ataxia. 

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2. Responses of Cortical Neurons to Intracortical Microstimulation in Awake Primates

   https://doi.org/10.1523/ENEURO.0336-22.2023  

   Yun, Richy ; Mishler, Jonathan H. ; Perlmutter, Steve I. ; Rao, Rajesh P. N. ; Fetz, Eberhard E. ( April 2023 , eneuro)

   Intracortical microstimulation (ICMS) is commonly used in many experimental and clinical paradigms; however, its effects on the activation of neurons are still not completely understood. To document the responses of cortical neurons in awake nonhuman primates to stimulation, we recorded single-unit activity while delivering single-pulse stimulation via Utah arrays implanted in primary motor cortex (M1) of three macaque monkeys. Stimuli between 5 and 50 μA delivered to single channels reliably evoked spikes in neurons recorded throughout the array with delays of up to 12 ms. ICMS pulses also induced a period of inhibition lasting up to 150 ms that typically followed the initial excitatory response. Higher current amplitudes led to a greater probability of evoking a spike and extended the duration of inhibition. The likelihood of evoking a spike in a neuron was dependent on the spontaneous firing rate as well as the delay between its most recent spike time and stimulus onset. Tonic repetitive stimulation between 2 and 20 Hz often modulated both the probability of evoking spikes and the duration of inhibition; high-frequency stimulation was more likely to change both responses. On a trial-by-trial basis, whether a stimulus evoked a spike did not affect the subsequent inhibitory response; however, their changes over time were often positively or negatively correlated. Our results document the complex dynamics of cortical neural responses to electrical stimulation that need to be considered when using ICMS for scientific and clinical applications.

    

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3. Creation of Neuronal Ensembles and Cell-Specific Homeostatic Plasticity through Chronic Sparse Optogenetic Stimulation

   https://doi.org/10.1523/JNEUROSCI.1104-22.2022  

   Liu, Benjamin ; Seay, Michael J. ; Buonomano, Dean V. ( November 2022 , The Journal of Neuroscience)

   Cortical computations emerge from the dynamics of neurons embedded in complex cortical circuits. Within these circuits, neuronal ensembles, which represent subnetworks with shared functional connectivity, emerge in an experience-dependent manner. Here we induced ensembles inex vivocortical circuits from mice of either sex by differentially activating subpopulations through chronic optogenetic stimulation. We observed a decrease in voltage correlation, and importantly a synaptic decoupling between the stimulated and nonstimulated populations. We also observed a decrease in firing rate during Up-states in the stimulated population. These ensemble-specific changes were accompanied by decreases in intrinsic excitability in the stimulated population, and a decrease in connectivity between stimulated and nonstimulated pyramidal neurons. By incorporating the empirically observed changes in intrinsic excitability and connectivity into a spiking neural network model, we were able to demonstrate that changes in both intrinsic excitability and connectivity accounted for the decreased firing rate, but only changes in connectivity accounted for the observed decorrelation. Our findings help ascertain the mechanisms underlying the ability of chronic patterned stimulation to create ensembles within cortical circuits and, importantly, show that while Up-states are a global network-wide phenomenon, functionally distinct ensembles can preserve their identity during Up-states through differential firing rates and correlations.

   SIGNIFICANCE STATEMENTThe connectivity and activity patterns of local cortical circuits are shaped by experience. This experience-dependent reorganization of cortical circuits is driven by complex interactions between different local learning rules, external input, and reciprocal feedback between many distinct brain areas. Here we used anex vivoapproach to demonstrate how simple forms of chronic external stimulation can shape local cortical circuits in terms of their correlated activity and functional connectivity. The absence of feedback between different brain areas and full control of external input allowed for a tractable system to study the underlying mechanisms and development of a computational model. Results show that differential stimulation of subpopulations of neurons significantly reshapes cortical circuits and forms subnetworks referred to as neuronal ensembles.

    

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4. Emergent Low-Frequency Activity in Cortico-Cerebellar Networks with Motor Skill Learning

   https://doi.org/10.1523/ENEURO.0011-23.2023  

   Fleischer, Pierson ; Abbasi, Aamir ; Fealy, Andrew W. ; Danielsen, Nathan P. ; Sandhu, Ramneet ; Raj, Philip R. ; Gulati, Tanuj ( February 2023 , eneuro)

   Abstract The motor cortex controls skilled arm movement by recruiting a variety of targets in the nervous system, and it is important to understand the emergent activity in these regions as refinement of a motor skill occurs. One fundamental projection of the motor cortex (M1) is to the cerebellum. However, the emergent activity in the motor cortex and the cerebellum that appears as a dexterous motor skill is consolidated is incompletely understood. Here, we report on low-frequency oscillatory (LFO) activity that emerges in cortico-cerebellar networks with learning the reach-to-grasp motor skill. We chronically recorded the motor and the cerebellar cortices in rats, which revealed the emergence of coordinated movement-related activity in the local-field potentials as the reaching skill consolidated. Interestingly, we found this emergent activity only in the rats that gained expertise in the task. We found that the local and cross-area spiking activity was coordinated with LFOs in proficient rats. Finally, we also found that these neural dynamics were more prominently expressed during accurate behavior in the M1. This work furthers our understanding on emergent dynamics in the cortico-cerebellar loop that underlie learning and execution of precise skilled movement. 

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5. A case study in the functional consequences of scaling the sizes of realistic cortical models.

   Joglekar, M. R. ; Chariker, L. ; Shapley, R. ; Young, L-S. ( July 2019 , PLoS computational biology)

   Tao, L (Ed.)

   Neuroscience models come in a wide range of scales and specificity, from mean-field rate models to large-scale networks of spiking neurons. There are potential trade-offs between simplicity and realism, versatility and computational speed. This paper is about large-scale cortical network models, and the question we address is one of scalability: would scaling down cell density impact a network’s ability to reproduce cortical dynamics and function? We investigated this problem using a previously constructed realistic model of the monkey visual cortex that is true to size. Reducing cell density gradually up to 50-fold, we studied changes in model behavior. Size reduction without parameter adjustment was catastrophic. Surprisingly, relatively minor compensation in synaptic weights guided by a theoretical algo- rithm restored mean firing rates and basic function such as orientation selectivity to models 10-20 times smaller than the real cortex. Not all was normal in the reduced model cortices: intracellular dynamics acquired a character different from that of real neurons, and while the ability to relay feedforward inputs remained intact, reduced models showed signs of defi- ciency in functions that required dynamical interaction among cortical neurons. These findings are not confined to models of the visual cortex, and modelers should be aware of potential issues that accompany size reduction. Broader implications of this study include the importance of homeostatic maintenance of firing rates, and the functional consequences of feedforward versus recurrent dynamics, ideas that may shed light on other species and on systems suffering cell loss. 

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