The Lyme disease spirochete Borrelia burgdorferi is unique among bacteria in its large number of lipoproteins that are encoded by a small, exceptionally fragmented, and predominantly linear genome. Peripherally anchored in either the inner or outer membrane and facing either the periplasm or the external environment, these lipoproteins assume varied roles. A prominent subset of lipoproteins functioning as the apparent linchpins of the enzootic tick-vertebrate infection cycle have been explored as vaccine targets. Yet, most of the B. burgdorferi lipoproteome has remained uncharacterized. Here, we comprehensively and conclusively localize the B. burgdorferi lipoproteome by applying established protein localization assays to a newly generated epitope-tagged lipoprotein expression library and by validating the obtained individual protein localization results using a sensitive global mass spectrometry approach. The derived consensus localization data indicate that 86 of the 125 analyzed lipoproteins encoded by B. burgdorferi are secreted to the bacterial surface. Thirty-one of the remaining 39 periplasmic lipoproteins are retained in the inner membrane, with only 8 lipoproteins being anchored in the periplasmic leaflet of the outer membrane. The localization of 10 lipoproteins was further defined or revised, and 52 surface and 23 periplasmic lipoproteins were newly localized. Cross-referencing prior studies revealed that the borrelial surface lipoproteome contributing to the hostpathogen interface is encoded predominantly by plasmids. Conversely, periplasmic lipoproteins are encoded mainly by chromosomal loci. These studies close a gap in our understanding of the functional lipoproteome of an important human pathogen and set the stage for more in-depth studies of thus-far-neglected spirochetal lipoproteins.IMPORTANCE The small and exceptionally fragmented genome of the Lyme disease spirochete Borrelia burgdorferi encodes over 120 lipoproteins. Studies in the field have predominantly focused on a relatively small number of surface lipoproteins that play important roles in the transmission and pathogenesis of this global human pathogen. Yet, a comprehensive spatial assessment of the entire borrelial lipoproteome has been missing. The current study newly identifies 52 surface and 23 periplasmic lipoproteins. Overall, two-thirds of the B. burgdorferi lipoproteins localize to the surface, while outer membrane lipoproteins facing the periplasm are rare. This analysis underscores the dominant contribution of lipoproteins to the spirochete's rather complex and adaptable host-pathogen interface, and it encourages further functional exploration of its lipoproteome.KEYWORDS cell envelope, lipoproteins, localization, membrane biogenesis, membrane proteins, outer membrane, protein secretion, proteomics, spirochetes, surface proteins
Current research in brain computer interface (BCI) technology is advancing beyond preclinical studies, with trials beginning in human patients. To date, these trials have been carried out with several different types of recording interfaces. The success of these devices has varied widely, but different factors such as the level of invasiveness, timescale of recorded information, and ability to maintain stable functionality of the device over a long period of time all must be considered in addition to accuracy in decoding intent when assessing the most practical type of device moving forward. Here, we discuss various approaches to BCIs, distinguishing between devices focusing on control of operations extrinsic to the subject (e.g., prosthetic limbs, computer cursors) and those focusing on control of operations intrinsic to the brain (e.g., using stimulation or external feedback), including closed-loop or adaptive devices. In this discussion, we consider the current challenges facing the translation of various types of BCI technology to eventual human application.
Intracortical microstimulation can be used successfully to modulate neuronal activity. Activity-dependent stimulation (ADS), in which action potentials recorded extracellularly from a single neuron are used to trigger stimulation at another cortical location (closed-loop), is an effective treatment for behavioral recovery after brain lesion, but the related neurophysiological changes are still not clear. Here, we investigated the ability of ADS and random stimulation (RS) to alter firing patterns of distant cortical locations. We recorded 591 neuronal units from 23 Long-Evan healthy anesthetized rats. Stimulation was delivered to either forelimb or barrel field somatosensory cortex, using either RS or ADS triggered from spikes recorded in the rostral forelimb area (RFA). Both RS and ADS stimulation protocols rapidly altered spike firing within RFA compared with no stimulation. We observed increase in firing rates and change of spike patterns. ADS was more effective than RS in increasing evoked spikes during the stimulation periods, by producing a reliable, progressive increase in stimulus-related activity over time and an increased coupling of the trigger channel with the network. These results are critical for understanding the efficacy of closed-loop electrical microstimulation protocols in altering activity patterns in interconnected brain networks, thus modulating cortical state and functional connectivity.
As our understanding of volitional motor function increases, it is clear that complex movements are the result of the interactions of multiple cortical regions rather than just the output properties of primary motor cortex. However, our understanding of the interactions among these regions is limited. In this study, we used the activity-dependent stimulation (ADS) technique to determine the short/long-term effects on network activity and neuroplasticity of intracortical connections. ADS uses the intrinsic neural activity of one region to trigger stimulations in a separate region of the brain and can manipulate neuronal connectivity in vivo. Our aim was to compare single-unit neuronal activity within premotor cortex (rostral forelimb area, [RFA] in rats) in response to ADS (triggered from RFA) and randomly-generated stimulation in the somatosensory area (S1) within single sessions and across 21 consecutive days of stimulation. We examined firing rate and correlation between spikes and stimuli in chronically-implanted healthy ambulatory rats during spontaneous and evoked activity. At the end of the treatment, we evaluated changes of synaptophysin expression. Our results demonstrated the ability of ADS to modulate RFA firing properties and to promote synaptogenesis in S1, strengthening the idea that this Hebbian-inspired protocol can be used to modulate cortical connectivity.
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