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Experience-dependent gene expression reshapes neural circuits, permitting the learning of knowledge and skills. Most learning involves repetitive experiences during which neurons undergo multiple stages of functional and structural plasticity. Currently, the diversity of transcriptional responses underlying dynamic plasticity during repetition-based learning is poorly understood. To close this gap, we analyzed single-nucleus transcriptomes of L2/3 glutamatergic neurons of the primary motor cortex after 3 d motor skill training or home cage control in water-restricted male mice. “Train” and “control” neurons could be discriminated with high accuracy based on expression patterns of many genes, indicating that recent experience leaves a widespread transcriptional signature across L2/3 neurons. These discriminating genes exhibited divergent modes of coregulation, differentiating neurons into discrete clusters of transcriptional states. Several states showed gene expressions associated with activity-dependent plasticity. Some of these states were also prominent in the previously published reference, suggesting that they represent both spontaneous and task-related plasticity events. Markedly, however, two states were unique to our dataset. The first state, further enriched by motor training, showed gene expression suggestive of late-stage plasticity with repeated activation, which is suitable for expected emergent neuronal ensembles that stably retain motor learning. The second state, equally found in both train and control mice, showed elevated levels of metabolic pathways and norepinephrine sensitivity, suggesting a response to common experiences specific to our experimental conditions, such as water restriction or circadian rhythm. Together, we uncovered divergent transcriptional responses across L2/3 neurons, each potentially linked with distinct features of repetition-based motor learning such as plasticity, memory, and motivation.

 

The meta-reinforcement learning (meta-RL) framework, which involves RL over multiple timescales, has been successful in training deep RL models that generalize to new environments. It has been hypothesized that the prefrontal cortex may mediate meta-RL in the brain, but the evidence is scarce. Here we show that the orbitofrontal cortex (OFC) mediates meta-RL. We trained mice and deep RL models on a probabilistic reversal learning task across sessions during which they improved their trial-by-trial RL policy through meta-learning. Ca²⁺/calmodulin-dependent protein kinase II-dependent synaptic plasticity in OFC was necessary for this meta-learning but not for the within-session trial-by-trial RL in experts. After meta-learning, OFC activity robustly encoded value signals, and OFC inactivation impaired the RL behaviors. Longitudinal tracking of OFC activity revealed that meta-learning gradually shapes population value coding to guide the ongoing behavioral policy. Our results indicate that two distinct RL algorithms with distinct neural mechanisms and timescales coexist in OFC to support adaptive decision-making.

 

Abstract Objective . Neural decoding is an important tool in neural engineering and neural data analysis. Of various machine learning algorithms adopted for neural decoding, the recently introduced deep learning is promising to excel. Therefore, we sought to apply deep learning to decode movement trajectories from the activity of motor cortical neurons. Approach . In this paper, we assessed the performance of deep learning methods in three different decoding schemes, concurrent, time-delay, and spatiotemporal. In the concurrent decoding scheme where the input to the network is the neural activity coincidental to the movement, deep learning networks including artificial neural network (ANN) and long-short term memory (LSTM) were applied to decode movement and compared with traditional machine learning algorithms. Both ANN and LSTM were further evaluated in the time-delay decoding scheme in which temporal delays are allowed between neural signals and movements. Lastly, in the spatiotemporal decoding scheme, we trained convolutional neural network (CNN) to extract movement information from images representing the spatial arrangement of neurons, their activity, and connectomes (i.e. the relative strengths of connectivity between neurons) and combined CNN and ANN to develop a hybrid spatiotemporal network. To reveal the input features of the CNN in the hybrid network that deep learning discovered for movement decoding, we performed a sensitivity analysis and identified specific regions in the spatial domain. Main results . Deep learning networks (ANN and LSTM) outperformed traditional machine learning algorithms in the concurrent decoding scheme. The results of ANN and LSTM in the time-delay decoding scheme showed that including neural data from time points preceding movement enabled decoders to perform more robustly when the temporal relationship between the neural activity and movement dynamically changes over time. In the spatiotemporal decoding scheme, the hybrid spatiotemporal network containing the concurrent ANN decoder outperformed single-network concurrent decoders. Significance . Taken together, our study demonstrates that deep learning could become a robust and effective method for the neural decoding of behavior. 

The inference of neuronal connectome from large-scale neuronal activity recordings, such as two-photon Calcium imaging, represents an active area of research in computational neuroscience. In this work, we developed FARCI (Fast and Robust Connectome Inference), a MATLAB package for neuronal connectome inference from high-dimensional two-photon Calcium fluorescence data. We employed partial correlations as a measure of the functional association strength between pairs of neurons to reconstruct a neuronal connectome. We demonstrated using in silico datasets from the Neural Connectomics Challenge (NCC) and those generated using the state-of-the-art simulator of Neural Anatomy and Optimal Microscopy (NAOMi) that FARCI provides an accurate connectome and its performance is robust to network sizes, missing neurons, and noise levels. Moreover, FARCI is computationally efficient and highly scalable to large networks. In comparison with the best performing connectome inference algorithm in the NCC, Generalized Transfer Entropy (GTE), and Fluorescence Single Neuron and Network Analysis Package (FluoroSNNAP), FARCI produces more accurate networks over different network sizes, while providing significantly better computational speed and scaling.