New Insights Into Activity-Dependent Transcription in the Brain

Abstract

Activity-dependent transcription instructs circuit wiring during nervous system development and mediates cell-type-specific adaptations of the mature brain to sensory stimuli. Despite these essential functions, much about the underlying mechanisms of activity-dependent transcription remains unresolved. The diversity of responses across the full range of cortical cell types, the molecular machinery that tunes these processes to ensure appropriate responses specifically during periods of heightened synaptic activity, and the consequences of aberrant transcription on neural circuits are all facets of activity-dependent transcription that require further exploration. To address these gaps in knowledge, we investigated in depth the molecular mechanisms that couple neuronal activity-dependent transcription to heightened synaptic activity, where such transcription regulates circuit excitatory-inhibitory balance through recruitment of somatic inhibition. We employed a suite of biochemical and sequencing-based approaches and found that in the absence of synaptic excitation, the transcription factor Arnt2 recruits the NCoR2 co-repressor complex to activity-dependent enhancers to restrict activity-dependent gene expression. Following neuronal activity, Arnt2 relieves Arnt2:NCoR2-mediated repression by recruiting the neuron-specific transcription factor Npas4. The interplay of these distinct complexes at activity-dependent enhancers maintains a context-appropriate level of gene expression, thereby scaling somatic inhibition according to circuit activity. We next applied single-cell RNA-sequencing to investigate the breadth of transcriptional changes that occur across all cell types in mouse visual cortex following light exposure. We identified divergent transcriptional responses to stimulation in each of the 30 cell types characterized and altogether identified 611 robustly stimulus-responsive genes. Excitatory neurons exhibit inter- and intralaminarly heterogeneous gene induction, while non-neuronal cells display responses that may regulate experience-dependent changes in neurovascular coupling and myelination. These results reveal the dynamic landscape of stimulus-dependent transcriptional changes in the visual cortex, which are likely critical for cortical function and may be sites of de-regulation in brain disorders. In summary, the work presented here comprises an advance in our understanding of activity-dependent transcription in the brain across two complementary dimensions: mechanistic depth, by characterizing the molecular complexes that modulate neural circuits through changes in transcription in excitatory neurons, and descriptive breadth, by examining the full span of all cell-type-specific responses in cortex to a single stimulus paradigm.