ALBERT

Description: Learning, whether motor, sensory or cognitive, requires networks of neurons to generate new activity patterns. As some behaviours are easier to learn than others, we asked if some neural activity patterns are easier to generate than others. Here we investigate whether an existing network constrains the patterns that a subset of its neurons is capable of exhibiting, and if so, what principles define this constraint. We employed a closed-loop intracortical brain-computer interface learning paradigm in which Rhesus macaques (Macaca mulatta) controlled a computer cursor by modulating neural activity patterns in the primary motor cortex. Using the brain-computer interface paradigm, we could specify and alter how neural activity mapped to cursor velocity. At the start of each session, we observed the characteristic activity patterns of the recorded neural population. The activity of a neural population can be represented in a high-dimensional space (termed the neural space), wherein each dimension corresponds to the activity of one neuron. These characteristic activity patterns comprise a low-dimensional subspace (termed the intrinsic manifold) within the neural space. The intrinsic manifold presumably reflects constraints imposed by the underlying neural circuitry. Here we show that the animals could readily learn to proficiently control the cursor using neural activity patterns that were within the intrinsic manifold. However, animals were less able to learn to proficiently control the cursor using activity patterns that were outside of the intrinsic manifold. These results suggest that the existing structure of a network can shape learning. On a timescale of hours, it seems to be difficult to learn to generate neural activity patterns that are not consistent with the existing network structure. These findings offer a network-level explanation for the observation that we are more readily able to learn new skills when they are related to the skills that we already possess.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4393644/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4393644/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sadtler, Patrick T -- Quick, Kristin M -- Golub, Matthew D -- Chase, Steven M -- Ryu, Stephen I -- Tyler-Kabara, Elizabeth C -- Yu, Byron M -- Batista, Aaron P -- P30 NS076405/NS/NINDS NIH HHS/ -- P30-NS076405/NS/NINDS NIH HHS/ -- R01 HD071686/HD/NICHD NIH HHS/ -- R01 NS065065/NS/NINDS NIH HHS/ -- R01-HD071686/HD/NICHD NIH HHS/ -- R01-NS065065/NS/NINDS NIH HHS/ -- England -- Nature. 2014 Aug 28;512(7515):423-6. doi: 10.1038/nature13665.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA [2] Center for the Neural Basis of Cognition, Pittsburgh, Pennsylvania 15213, USA [3] Systems Neuroscience Institute, University of Pittsburgh, Pittsburgh Pennsylvania 15261, USA. ; 1] Center for the Neural Basis of Cognition, Pittsburgh, Pennsylvania 15213, USA [2] Department of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA. ; 1] Center for the Neural Basis of Cognition, Pittsburgh, Pennsylvania 15213, USA [2] Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA. ; 1] Department of Electrical Engineering, Stanford University, Stanford, California 94305, USA [2] Department of Neurosurgery, Palo Alto Medical Foundation, Palo Alto, California 94301, USA. ; 1] Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA [2] Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA [3] Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. ; 1] Center for the Neural Basis of Cognition, Pittsburgh, Pennsylvania 15213, USA [2] Department of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA [3] Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA [4]. ; 1] Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA [2] Center for the Neural Basis of Cognition, Pittsburgh, Pennsylvania 15213, USA [3] Systems Neuroscience Institute, University of Pittsburgh, Pittsburgh Pennsylvania 15261, USA [4].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25164754" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yu, Byron M -- England -- Nature. 2016 Apr 28;532(7600):449-50. doi: 10.1038/nature17886. Epub 2016 Apr 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Electrical and Computer Engineering and the Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27074510" target="_blank"〉PubMed〈/a〉

Description: The association of DSIF and NELF with initiated RNA Polymerase II (Pol II) is the general mechanism for inducing promoter-proximal pausing of Pol II. However, it remains largely unclear how the paused Pol II is released in response to stimulation. Here, we show that the release of the paused Pol II is cooperatively regulated by multiple P-TEFbs which are recruited by bromodomain-containing protein Brd4 and super elongation complex (SEC) via different recruitment mechanisms. Upon stimulation, Brd4 recruits P-TEFb to Spt5/DSIF via a recruitment pathway consisting of Med1, Med23 and Tat-SF1, whereas SEC recruits P-TEFb to NELF-A and NELF-E via Paf1c and Med26, respectively. P-TEFb-mediated phosphorylation of Spt5, NELF-A and NELF-E results in the dissociation of NELF from Pol II, thereby transiting transcription from pausing to elongation. Additionally, we demonstrate that P-TEFb-mediated Ser2 phosphorylation of Pol II is dispensable for pause release. Therefore, our studies reveal a co-regulatory mechanism of Brd4 and SEC in modulating the transcriptional pause release by recruiting multiple P-TEFbs via a Mediator- and Paf1c-coordinated recruitment network.