Ernst Strüngmann Forum

Navigation Research: Mapping the Future

Nora S. Newcombe and Ken Cheng, Chairs

How animals navigate, for example, across complex terrain, featureless oceans, or deserts to find their way home after a foraging trip has long fascinated and puzzled observers. Successful navigation is essential to survival. Thus, understanding its mechanisms has long been a major goal for researchers in biology, neuroscience, psychology, and robotics. Easing the task of wayfinding has also been the focus for the practical inventors of human navigational tools, which have ranged from traditional systems using a complex mix of terrestrial and celestial cues to modern global positioning systems. A wealth of behavioral and neural data has been generated, which when combined with formal computational specificity offers an excellent opportunity to formulate pluralistic explanations might link brain and behavior as well as relate behavioral patterns to neural firing patterns.

The field of navigation, however, has been fragmented, with little communication across disciplines and levels of analysis. For example, neuroscientists recording cells may not think about, or find it difficult to tackle experimentally, the ecological validity of the behaviors their animals engage in, while biologists seeking to understand natural behavior may not consider the neural substrates supporting it, limiting their hypotheses. One reason for this fragmentation is that the variety of findings and wealth of data generated by these endeavors can be overwhelming. This Forum aims to address this issue by synthesizing what is known and identifying the major gaps in our understanding in order to drive future research.

More Info

Metabolic Neuropsychiatry

Dost Öngür and Judith Ford, Chairs

Energy metabolism and related processes play a critical role in supporting and regulating brain function. Much of the energy generated in the brain is used to support action potential generation and synaptic transmission—the basic mechanisms of nerve cell communication. This realization has led to renewed interest in the role that energy metabolism plays in both healthy brain function and in the emergence of brain disorders, with the hope that improving energy metabolism may lead to treatments for brain conditions for which existing treatments are unsatisfactory.

Several lines of research provide converging evidence that neuropsychiatric disorders (schizophrenia, neurodegenerative disorders, and autism) are characterized by abnormal brain bioenergetics—evidence from GWAS of neuropsychiatric disorders, abnormal energy metabolism in patient-derived samples, reduced expression of mitochondrial markers in patient-derived postmortem brain tissue, and in vivo neuroimaging studies indicating reduction in the synthesis and utilization of ATP coupled with a shift from high-efficiency oxidative phosphorylation to inefficient glycolysis for energy production. These bioenergetic abnormalities are best conceptualized as part of a set of interconnected biochemical processes, including abnormal redox biology and neuroinflammation, which together impair brain function in various ways. Although the exact mechanisms linking abnormal brain bioenergetics to neuropsychiatric dysfunction are not well delineated, spatial and temporal aberrations in availability of energy supply may lead to abnormal neural signaling. Depending on the details of bioenergetic dysfunction in subcellular location, affected cell-types, and available compensatory mechanisms, this basic theme may manifest itself in deviation from expected developmental trajectories in early life, abnormal information processing in midlife, and accelerated neurodegeneration in late life.

Abnormal brain bioenergetics is receiving increased attention because of the potential for developing new treatment interventions. A large body of research in diabetes and other metabolic disorders has led to a deep understanding of energy metabolism and to effective diet/exercise and medication treatments to correct metabolic abnormalities, but until now has not been studied systematically in neuropsychiatry.

Reports of clinical improvement in response to the ketogenic diet in individuals with severe mental illnesses become relevant in this context. The ketogenic diet is an FDA-approved treatment for childhood epilepsy in the U.S., and several reports have linked it with positive outcomes in other brain disorders. Several large-scale studies are currently underway to test the effect of this diet and various other metabolic interventions in neuropsychiatric disorders, and more are expected. These developments provide hope that it may be possible to leverage metabolic interventions to improve outcomes in neuropsychiatric disorders. Greater focus on brain metabolism may also lead to the development of new treatments that are easier to administer, more efficacious, and associated with fewer adverse effects.

Are metabolic abnormalities seen in neuropsychiatric disorders restricted to the brain or are they systemic? Most evidence would suggest the latter, a point further highlighted by the well-known propensity of patients with neuropsychiatric disorders to develop metabolic syndrome. Since the same factors that contribute to the emergence of abnormal brain function may also contribute to a higher burden of medical conditions such as diabetes, obesity, and hypertension, this is an important area of focus in neuropsychiatric disorders not only to improve psychiatric outcomes but also to prevent medical morbidity and mortality.

More Info