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Sleep is known to be important for promoting recovery after brain injuries such as stroke. Yet, it remains unclear how such injuries affect neural processing during sleep and how to precisely enhance sleep-dependent memory processing during recovery. Using an experimental model of focal cortical stroke in rats along with long-term electrophysiological monitoring of neural firing and sleep microarchitecture, here we show that sleep-dependent neural processing is altered after stroke induction. Specifically, we found that the precise coupling of spindles to global slow- oscillations (SO), a phenomenon that is known to be important for memory consolidation, appeared to be disrupted by a pathological increase in “isolated” local delta waves. The transition from this pathological to a more physiological sleep state – with both a reduction in isolated delta waves and increased spindle coupling to SO – was associated with sustained performance gains after task training during recovery. Interestingly, post-injury sleep processing could be pushed towards a more physiological state via a pharmacological reduction of tonic GABA. Together, our results suggest that sleep processing after cortical brain injuries may be impaired due to an increase in local delta waves and that restoration of physiological processing is important for recovery of task performance.

The axon initial segment (AIS) is a specialized neuronal compartment in which synaptic input is converted into action potential (AP) output. This process is supported by a diverse complement of sodium, potassium, and calcium channels (CaV). Different classes of sodium and potassium channels are scaffolded at specific sites within the AIS, conferring unique functions, but how calcium channels are functionally distributed within the AIS is unclear. Here, we use conventional two-photon laser scanning and diffraction-limited, high-speed spot two-photon imaging to resolve AP-evoked calcium dynamics in the AIS with high spatiotemporal resolution. In mouse layer 5 prefrontal pyramidal neurons, calcium influx was mediated by a mix of CaV2 and CaV3 channels that differentially localized to discrete regions. CaV3 functionally localized to produce nanodomain hotspots of calcium influx that coupled to ryanodine-sensitive stores, whereas CaV2 localized to non-hotspot regions. Thus, different pools of CaVs appear to play distinct roles in AIS function.SIGNIFICANCE STATEMENTThe axon initial segment (AIS) is the site where synaptic input is transformed into action potential (AP) output. It achieves this function through a diverse complement of sodium, potassium, and calcium channels (CaV). While the localization and function of sodium channels and potassium channels at the AIS is well described, less is known about the functional distribution of CaVs. We used high-speed two-photon imaging to understand activity-dependent calcium dynamics in the AIS of mouse neocortical pyramidal neurons. Surprisingly, we found that calcium influx occurred in two distinct domains: CaV3 generates hotspot regions of calcium influx coupled to calcium stores, whereas CaV2 channels underlie diffuse calcium influx between hotspots. Therefore, different CaVclasses localize to distinct AIS subdomains, possibly regulating distinct cellular processes.

Plasticity within the corticostriatal network is known to regulate the balance between behavioral flexibility and automaticity. Repeated training of an action has been shown to bias behavior towards automaticity, suggesting that training may trigger activity-dependent corticostriatal plasticity. However, surprisingly little is known about the natural activity patterns that may drive plasticity or when they occur during long-term training. Here we chronically monitored neural activity from primary motor cortex (M1) and the dorsolateral striatum (DLS) during both training and offline periods, i.e., time away from training including sleep, throughout the development of an automatic reaching action. We first show that blocking striatal NMDA receptors during offline periods prevents the emergence of behavioral consistency, a hallmark of automaticity. We then show that, throughout the development of an automatic reaching action, corticostriatal functional connectivity increases during offline periods. Such increases track the emergence of consistent behavior and predictable cross-area neural dynamics. We then identify sleep spindles during non-REM sleep (NREM) as uniquely poised to mediate corticostriatal plasticity during offline periods. We show that sleep spindles are periods of maximal corticostriatal transmission within offline periods, that sleep spindles in post-training NREM reactivate neurons across areas, and that sleep-spindle modulation in post-training NREM is linked to observable changes in spiking relationships between individual pairs of M1 and DLS neurons. Our results indicate that offline periods, in general, and sleep spindles, specifically, play an important role in regulating behavioral flexibility through corticostriatal network plasticity.

Neural implants with large numbers of electrodes have become an important tool for examining brain functions. However, these devices typically displace a large intracranial volume compared to the neurons they record. This large size limits the density of implants, provokes tissue reactions that degrade chronic performance, and impedes the ability to accurately visualize recording sites within intact circuits. Here we report next-generation silicon-based neural probes at cellular-scale (5×10µm cross-section), with ultra-high-density packing (as little as 66µm between shanks) and 64 or 256 closely-spaced recording sites per probe. We show that these probes can be inserted into superficial or deep brain structures and maintain high-quality spike recordings in freely behaving rats for many weeks. Finally, we demonstrate a slice-in-place approach for the precise registration of recording sites relative to nearby neurons and anatomical features, including striatal µ-opioid receptor patches. This scalable technology provides a valuable tool for examining information processing within neural circuits, and potentially for human brain-machine interfaces.

SARS-CoV-2, the pandemic coronavirus that causes COVID-19, has infected millions worldwide, causing unparalleled social and economic disruptions. COVID-19 results in higher pathogenicity and mortality in the elderly compared to children. Examining baseline SARS-CoV-2 cross-reactive coronavirus immunological responses, induced by circulating human coronaviruses, is critical to understand such divergent clinical outcomes. The cross-reactivity of coronavirus antibody responses of healthy children (n=89), adults (n=98), elderly (n=57), and COVID-19 patients (n=19) were analysed by systems serology. While moderate levels of cross-reactive SARS-CoV-2 IgG, IgM, and IgA were detected in healthy individuals, we identified serological signatures associated with SARS-CoV-2 antigen-specific Fcγ receptor binding, which accurately distinguished COVID-19 patients from healthy individuals and suggested that SARS-CoV-2 induces qualitative changes to antibody Fc upon infection, enhancing Fcγ receptor engagement. Vastly different serological signatures were observed between healthy children and elderly, with markedly higher cross-reactive SARS-CoV-2 IgA and IgG observed in elderly, whereas children displayed elevated SARS-CoV-2 IgM, including receptor binding domain-specific IgM with higher avidity. These results suggest that less-experienced humoral immunity associated with higher IgM, as observed in children, may have the potential to induce more potent antibodies upon SARS-CoV-2 infection. These key insights will inform COVID-19 vaccination strategies, improved serological diagnostics and therapeutics.