Gero Miesenböck is giving the 2018 Francis Crick Lecture at the MRC Laboratory of Molecular Biology in Cambridge on 24 October. The Crick Lecture, named in honour of the late LMB Nobel Laureate, is one of a series of named lectures organised by the LMB to be given by eminent scientists from around the world.
Abstract: The synaptic connectome of the nematode C. elegans has been mapped completely, and efforts are ongoing to map the connectomes of other animals. However, chemical synapses represent only one of several types of signaling interaction in the nervous system. In particular, neuromodulation by monoamines, neuropeptides, or classical neurotransmitters is widespread and often occurs extrasynaptically between neurons not connected by wired synapses. In C. elegans, it is feasible to map these neuromodulatory networks comprehensively and at a single-cell level and examine how wired and wireless signaling interact. In this talk, I will describe what we have learned about the functional organisation of neuromodulatory circuitry involved in the control of behavioural states such as arousal, as well as our ongoing efforts to map extrasynaptic connectome networks comprehensively in the worm. In addition, I will discuss our identification of new ionotropic receptors for monoamines and other neuromodulators, which may represent novel targets for anti-parasitic drugs.
Biography: Bill Schafer studied Biology at Harvard University, then moved to UC Berkeley for graduate studies in Biochemistry. His PhD thesis in the lab of Jasper Rine described the role of protein prenylation in yeast mating factors and Ras proteins. His postdoctoral research in the lab of Cynthia Kenyon at UCSF investigated the effects of monoamines on behaviour. In 1995, he established his own group in the Division of Biology at UCSD, and in 2006 moved to the LMB in Cambridge. His independent research has focused on the elucidation of neural circuit mechanisms using genetically-encoded optical indicators, the molecules of somatosensation, and the quantitative analysis of behavioural phenotypes. Recent work has investigated the molecular, cellular, and network-level mechanisms of neuromodulation in simple connectomes. He is a fellow of the Academy of Medical Sciences, a member of EMBO, a Wellcome Senior Investigator, and has been the receipient of a Presidential Early Career Award from the NIH.
Subthreshold changes in membrane voltage represent accumulating evidence before a choice. The transcription factor FoxP sets neuronal integration and behavioural decision times.
Decisions take time because the information needed to make them is rarely available all at once but must be gathered sequentially. We know from our own experience that decisions tend to be quick when the choice is unambiguous but protracted when evidence is weak or conflicting. This difficulty-dependent cost of decision time is thought to reflect an underlying need to construct time-averaged sensory representations. Just as engineers average signals over time to reduce the effects of contaminating noise, the brain appears to improve its signal-to-noise ratio by integrating information from sequential samples. The neural structures and mechanisms responsible for this integration process remain incompletely understood.
In experiments asking fruit flies to distinguish between ever closer concentrations of an odour, the Miesenböck group had previously identified a tiny minority of about 200 neurons (out of 100,000 in the brain) as critical determinants of decision time.
In new work reported in the journal Cell, the team found that these neurons collect evidence for the alternative choices as minute voltage changes across their plasma membranes. These changes build up over time until they reach a hair-trigger point, at which the neurons produce an explosive action potential discharge. This discharge signals that a decision has been reached.
‘We have discovered a simple physical basis for a cognitive process,’ says the lead author of the study, Lukas Groschner. ‘Our work suggests that there is an important analogue component to cognition. People sometimes compare the brain to a digital machine operating with sequences of electrical impulses and silences. But much of what looks like silence is actually taken up by analogue computation.’
The decision-relevant neurons are distinguished by the presence of a genetic regulator molecule called FoxP.
FoxP determines how evidence is added and retained. Flies with defective FoxP produce too much of a potassium channel that acts like a shock absorber and makes the cells’ voltage less noisy, but also less likely to change with each new piece of information. Decisions therefore take longer—the flies become indecisive.
Fruit flies have one FoxP gene, while humans have four related genes. Human FoxP1 and FoxP2 have been associated with intelligence and cognitive development, hinting at commonalities.
‘Fruit flies have an impressive record for making seemingly impenetrable biological problems tractable,’ says Miesenböck. ‘I wouldn’t be surprised if, in the next 20 years or so, they will do for cognitive science what they did for developmental biology in the recent past.’
Dendritic integration of sensory evidence in perceptual decision-making by Lukas N. Groschner, Laura Chan Wah Hak, Rafal Bogacz, Shamik DasGupta and Gero Miesenböck. Cell (2018)
Gero Miesenböck was awarded the degree of Doctor of Science honoris causa by Trinity College Dublin.