Non-overlapping cell populations within dorsomedial prefrontal cortex (dmPFC), defined by gene expression or projection target, control dissociable aspects of reward seeking through unique activity patterns. However, even within these defined cell populations considerable cell-to-cell variability is found, suggesting that greater resolution is needed to understand information processing in dmPFC. Here we use two-photon calcium imaging in awake, behaving mice to monitor the activity of dmPFC excitatory neurons throughout Pavlovian reward conditioning. We characterize five unique neuronal ensembles that each encode specialized information related to a sucrose reward, reward-predictive cues, and behavioral responses to those cues. The ensembles differentially emerge across daily training sessions - and stabilize after learning - in a manner that improves the predictive validity of dmPFC activity dynamics for deciphering variables related to behavioral conditioning. Our results characterize the complex dmPFC neuronal ensemble dynamics that stably predict reward availability and initiation of conditioned reward seeking following cue-reward learning.
All data generated for this study are available on Dryad Digital Repository, accessible here: https://doi.org/10.5061/dryad.xksn02vg8. We are in the process of uploading raw videos for these data to the Image Data Resource (https://idr.openmicroscopy.org/), as there is a 3 week lead time to get the data uploaded and special considerations are required for datasets of >1TB. Code will be uploaded to GitHub upon publication. All data, code, and raw imaging files will be uploaded to these open-source repositories prior to publication.
Behavioral and Imaging data for: Grant et al. (2021). Specialized coding patterns among dorsomedial prefrontal neuronal ensembles predict conditioned reward seekingDryad Digital Repository, doi:10.5061/dryad.xksn02vg8.
- James M Otis
- Roger I Grant
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: Experiments were performed in the dark phase and in accordance with the NIH Guide for the Care and Use of Laboratory Animals with approval from the Institutional Animal Care and Use Committee at the Medical University of South Carolina (Approval ID: IACUC-2018-00363; Renewed November 30, 2020).
- Mario Penzo, National Institute of Mental Health, United States
© 2021, Grant et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
De novo mutations in voltage- and ligand-gated channels have been associated with an increasing number of cases of developmental and epileptic encephalopathies, which often fail to respond to classic antiseizure medications. Here, we examine two knock-in mouse models replicating de novo sequence variations in the HCN1 voltage-gated channel gene, p.G391D and p.M153I (Hcn1G380D/+ and Hcn1M142I/+ in mouse), associated with severe drug-resistant neonatal- and childhood-onset epilepsy, respectively. Heterozygous mice from both lines displayed spontaneous generalized tonic-clonic seizures. Animals replicating the p.G391D variant had an overall more severe phenotype, with pronounced alterations in the levels and distribution of HCN1 protein, including disrupted targeting to the axon terminals of basket cell interneurons. In line with clinical reports from patients with pathogenic HCN1 sequence variations, administration of the antiepileptic Na+ channel antagonists lamotrigine and phenytoin resulted in the paradoxical induction of seizures in both mouse lines, consistent with an effect to further impair inhibitory neuron function. We also show that these variants can render HCN1 channels unresponsive to classic antagonists, indicating the need to screen mutated channels to identify novel compounds with diverse mechanism of action. Our results underscore the necessity of tailoring effective therapies for specific channel gene variants, and how strongly validated animal models may provide an invaluable tool towards reaching this objective.
Sleep and plasticity are highly interrelated, as sleep slow oscillations and sleep spindles are associated with consolidation of Hebbian-based processes. However, in adult humans, visual cortical plasticity is mainly sustained by homeostatic mechanisms, for which the role of sleep is still largely unknown. Here we demonstrate that non-REM sleep stabilizes homeostatic plasticity of ocular dominance induced in adult humans by short-term monocular deprivation: the counter-intuitive and otherwise transient boost of the deprived eye was preserved at the morning awakening (>6 hours after deprivation). Subjects exhibiting a stronger boost of the deprived eye after sleep had increased sleep spindle density in frontopolar electrodes, suggesting the involvement of distributed processes. Crucially, the individual susceptibility to visual homeostatic plasticity soon after deprivation correlated with the changes in sleep slow oscillations and spindle power in occipital sites, consistent with a modulation in early occipital visual cortex.