Kavli Blog

The Journal of Neuroscience recently published two commentaries on neuroethics for the NIH BRAIN Initiative: a set of eight guiding principles for neuroethical considerations in neuroscience research, as well as an accompanying commentary on neuroethics strategy and operationalization from NIH Institute Directors involved in BRAIN. 

The ethical imperative surrounding the pursuit of neuroscience research, and the critical integration of neuroethics into that research, underscore the importance of considering the ethical, legal, and societal implications of scientific study. From the beginning, the NIH BRAIN Initiative has worked diligently to integrate neuroethics into its science, motivated by the understanding that brain circuit activity forms the foundation of human experiences (e.g., perception, thought, action), which is uniquely entwined with our sense of personal identity.

In recognition of the many important ethical questions related to the conduct and use of neuroscience research, NIH established the Neuroethics Working Group (NEWG), comprised of both neuroethicists and neuroscientists. This group provides expert input on neuroethics, and helps to ensure that neuroethical considerations are fully integrated into the Initiative.

To foster ongoing and engaging dialogue surrounding ethics in neuroscience research, the NEWG has published guiding neuroethical principles for the NIH BRAIN Initiative. These eight principles (see Figure below) provide an overarching framework that can help inform dialogues among stakeholders, including investigators, clinicians, institutional review boards, funders, research participants, patients, and the public, both in the design and conduct of research as they grapple with ethical questions elicited by the Initiative that call for wider discussion and deeper understanding.

For example, scientists sometimes conduct in vivo neuroscience research with patients undergoing neurosurgery for clinical indications. Several of the guiding principles help to frame ethical questions associated with this kind of research, including 1. Making assessing safety paramount; 2. Anticipating special issues related to capacity, autonomy, and agency; 3. Protecting the privacy and confidentiality of neural data; and 6. Identifying and addressing specific concerns of the public about the brain. In particular, Principle 2 presents a unique neuroethical issue – namely, how precise modulation of circuit function might affect a person’s autonomy, agency, and identity. In this research space, the neuroethics guiding principles can help researchers to navigate potentially challenging questions that arise. For more information, please view the videocast of the NEWG symposium on this topic.

Accompanying these guiding principles is a commentary from NIH Institute Directors involved in the NIH BRAIN Initiative, outlining the neuroethics strategy and operationalization of neuroethics integration into the NIH BRAIN Initiative’s research portfolio.

These guiding principles offer points of consideration, as researchers and other stakeholders navigate the difficult questions that BRAIN Initiative research will pose to society. Alongside this ongoing dialogue, a robust neuroethics infrastructure will help ensure that neuroscience research is held to the highest ethical standards for the public that it serves.

The NIH BRAIN Initiative continues to seek input through a Request for Information (RFI) from key stakeholders on how to best accomplish the ambitious scientific vision of the Initiative.

As mentioned in an earlier announcement, the ACD (Advisory Committee to the NIH Director) BRAIN Initiative Working Group 2.0, co-chaired by Dr. Catherine Dulac (Harvard University) and Dr. John Maunsell (University of Chicago) held a series of three public, cross-country workshops and a public town hall to solicit input and expert consultations from leaders in the field, as well as to hear from stakeholders in the scientific community and the general public.

For detailed, updated information about these workshops and town hall, including links to the workshop agendas and videocasts, please visit: https://www.braininitiative.nih.gov/strategic-planning/acd-working-group.

Importantly, NIH has been seeking feedback on the BRAIN Initiative’s progress and on opportunities moving forward, given the current state of the science. The ACD BRAIN Initiative Working Group 2.0 will consider this input, as it provides scientific guidance to the ACD on how best to continue to accelerate the ambitious vision for the BRAIN Initiative.

Please submit your feedback! To assure full consideration by the ACD WG, please submit responses by November 15, 2018. Responses beyond this date will be accepted and incorporated on an ad hoc basis. To submit a response, visit the BRAIN Request for Information (RFI) (www.braininitiative.nih.gov/rfi.aspx) or provide feedback via email to BRAINFeedback@nih.gov.

Please join us for exciting BRAIN-relevant events at the annual Society for Neuroscience meeting in San Diego, CA (November 3rd-7th).

The ACD (Advisory Committee to the NIH Director) BRAIN Initiative Working Group 2.0, co-chaired by Dr. Catherine Dulac (Harvard University) and Dr. John Maunsell (University of Chicago), has been assessing BRAIN’s progress and advances within the context of the original BRAIN 2025 report, in order to identify key opportunities to apply new and emerging tools to revolutionize our understanding of brain circuits, and designate valuable areas of continued technology development. Part of the Working Group’s efforts included a series of public, cross-country workshops to solicit input and expert consultations from leaders in the field, as well as to hear from stakeholders in the scientific community and the general public. For more information, including links to the archived videocasts, visit here. As its next event, the Working Group will hold a public town hall and networking session at the upcoming Society for Neuroscience meeting.

The ACD BRAIN Initiative Working Group Town Hall with BRAIN Initiative Alliance Networking Event will occur on Sunday, November 4th, from 6:30pm-9:00pm (PST) at the Marriott Marquis, San Diego Ballrooms B and C. This open event, sponsored by the BRAIN Initiative Alliance, will solicit input on the planning efforts of the Working Group. It will offer the opportunity for BRAIN Initiative grantees, BRAIN Initiative Alliance members, interested researchers, and other public/private groups, to meet the Working Group, network, and learn more about the BRAIN Initiative and its wide range of public and private BRAIN funders. For those unable to attend in person, the videocast of the town hall portion of the event may be accessed here. You can submit your feedback here.

The day before the Town Hall event, The Brain Bash: Celebrating the International Brain Initiative reception will occur on Saturday, November 3rd, from 6:30pm-9:00pm (PST) at the Marriott Marquis, San Diego Ballroom F. Countries around the world are investing in basic research to transform our knowledge of the brain. All are welcome to join this event that will include a short presentation to learn about the International Brain Initiative (IBI) and the launch of the IBI website, as well as to discuss ideas for how the IBI can foster coordination across countries in areas such as: neuroethics, data sharing, and education/training.

These and other events can be found on the BRAIN Initiative Alliance website: http://www.braininitiative.org/events/. We hope to see you in San Diego!

Multiscale structural mapping of mouse hippocampus … Bayesian inference and variability in a songbird model of learning … Single-fluorophore biosensors enable sensitive detection of kinase dynamics …

Integration of gene expression yields comprehensive, multiscale map of mouse hippocampus

The hippocampus – one of the most studied parts of the brain at the level of synaptic physiology and plasticity – has been linked to spatial navigation and cognitive function, as well as emotional and affective behaviors. It is one of the first parts of the brain impaired by Alzheimer’s disease, and hippocampal degeneration is also linked to epilepsy and other diseases. Therefore, thorough knowledge of its structure is critical towards a complete understanding of its function and relationship to disease. Physiological studies in both humans and rodents have suggested structural and functional heterogeneity along the longitudinal axis of the hippocampus. To understand mouse hippocampal gene expression and anatomical connectivity, Dr. Hong-Wei Dong and colleagues at the University of Southern California mapped the distribution of >250 genes expressed throughout the hippocampus and subiculum, creating the Hippocampus Gene Expression Atlas (HGEA). HGEA provides the first coherent anatomical and gene expression-based framework for mouse hippocampal network connectivity, reconciling previous, differing interpretations of gene expression and hippocampal organization. Results suggest marked similarity between HGEA subdivisions and anatomical label patterns, leading to a multiscale organization whereby HGEA subregions contribute to small hippocampal subnetworks that, in turn, constitute larger “dorsal” and “ventral” subnetworks. Importantly, the HGEA provides an anatomical and gene expression roadmap by which a structural foundation for network connectivity can guide functional dissection of the hippocampus. This can pave the way for a “dynamic” connectome tightly linked to hippocampal structure and function. For more information, please see the USC press release on this work.

Experimental workflow. (top) HGEA subregions were defined and mapped onto an atlas, based on multiple gene expressions and consensus of subregion boundaries. (bottom) Following atlas creation, connectivity of each HGEA subregion was examined, using combinations of multiple retrograde and anterograde tracers and a variety of experimental strategies, including computational network analysis.

New theory posits that songbirds use Bayesian inference in vocal learning

Navigating the world successfully requires learning behaviors – reaching for objects, speaking, walking, and countless others. These skilled behaviors are learned through a series of trial and error. However, existing theories of learning have difficulty explaining exactly how learning depends on the error signals, for example, that smaller sensory errors are more readily corrected than larger errors and large abrupt (but not gradually introduced) errors lead to weak learning. Drs. Samuel Sober, Ilya Nemenman, and a team of colleagues at Emory University proposed and tested a new theory of sensorimotor learning that better predicts how learning depends on the error signals.

(A) Schematic of sensorimotor learning. (B) Photograph of Bengalese finch with headphones that are used to deliver manipulated feedback in real time. (Figure from Sober & Brainard, PNAS, 2012)

According to the theory, the brain controls a distribution of motor commands, rather than a single optimal command, in the face of sensory and motor noise, as most learning theories assume. The distribution is then updated through Bayesian inference as new information becomes available, resulting in learning. Using vocal adaptation in the Bengalese finch as a model system of learning, the researchers observed that male songbirds exhibited much smaller pitch variability when song was directed towards a female, compared to an undirected song, suggesting deliberate control of song variability rather than a single optimal motor command. Additionally, when the researchers systematically changed the perceived tones that the songbirds heard, they found that pitch distribution changed from unimodal to bimodal, suggesting a dynamic approach by which the songbirds deliberately explored a range of plausible motor commands. This novel theory explains the observed dependence of learning on the dynamics of sensory errors, with wide-ranging potential for further tests in other model systems and species.

(Left) The distribution of pitch – before any pitch shift perturbations. (Right) The model predicts – and shows – that after perturbation, the pitch distribution is bimodal, reflecting two peaks centered far from each other. (Figure from Zhou et al., PNAS, 2018)

Single-fluorophore biosensors enable dynamic monitoring of protein activity

To gain a comprehensive picture of cell behavior, and particularly the dynamics of molecular interplay that give rise to function, scientists have harnessed the power of optical tools, including biosensors that enable direct visualization of multiple dynamic biochemical processes. However, these methods are limited to imaging activities in isolation, or at most, monitoring 2-4 activities in parallel. To address this issue, Dr. Richard Huganir and a team of investigators from the University of California San Diego, Peking University, and the John Hopkins University School of Medicine developed a suite of single-fluorophore biosensors for monitoring dynamic kinase activities, allowing accurate measurement and monitoring of multiple signaling activities in living cells. The researchers first developed and characterized a kinase sensor that showed moderate-to-strong fluorescence at 380-480 nm, allowing for dynamic and specific detection of protein kinase A (PKA) activity in living cells. They were then able to couple PKA signaling to growth factor signaling, improving the range of the sensor within the cell, and maximizing the ability to image multiple proteins at once. By combining biosensor probes to fluorophores of different colors and targeting sensors to non-overlapping subcellular structures, the researchers simultaneously monitored up to six different dynamic cellular processes via multiplex imaging. These included kinases such as cAMP/PKA, PKC, and ERK. Subtle shifts in kinase activity often underlie important physiological processes, including synaptic plasticity. This novel toolkit provides an important method for obtaining a better understanding of kinase activity dynamics in living cells, allowing us to understand complex cellular processes in their physiological context.

These single-fluorophore biosensors can be expanded and combined with single-fluorophore probes of different colors. Simultaneously monitoring changes in protein activity and elevations is possible, with even further multiplexing achieved by physical separation of biosensors via targeting to non-overlapping subcellular structures, allowing six-fold multiplexing. Here, successful monitoring of membrane- and nuclear-localized PKA and ERK activity occurs alongside cytosolic cAMP and Ca2+ accumulation in single living cells.