NEUROTALKS

Neuroimplants: Theory, experiment and clinical application The application of neuroimplants has been a dream for decades in order to improve or substitute an entire sensual system. Nowadays clinically relevant neuroimplants for sensory systems are available only to aid the auditory system and are namely cochlear implants (CI), auditory brainstem implants (ABI) and auditory midbrain implants (AMI). Despite the tremendous success of cochlear implants, patients still suffer from difficulties in acoustically adverse environment in understanding speech and in the appraisal of music. One reason for this is that cochlear implants lack the proper provision of temporal information. Therefore, research focuses on the improvement of temporal information transfer. Simulation results (Bahmer and Langner, 2006 I + II, 2009) do imply that temporal information transfer may be improved by broadband electrical stimulation. Rate pitch discrimination experiments in CI-users show an improvement in the broad electrical field condition but this effect was not statistically significant due to the high variability in subject performances (Bahmer and Baumann, 2012). Thus, we developed physiological test setups which cope with electrical artifacts induced by the electrical stimulation of the implant (Bahmer and Baumann, 2008, 2010).

The receptive field hypothesis (RFH) is the idea that the response of a neuron to any spatial pattern can be predicted from the sensitivity map across its receptive field. For instance, the RFH predicts that a visual neuron s response to an edge in a visual image s lightness pattern can be predicted from the location of the edge in the neuron s receptive field. The RFH works very well when applied to retinal ganglion cells in the cat or monkey retinas, and to some neurons in the visual cortex. But we (Yeh, Xing, Williams and Shapley) found that the RFH fails for most neurons in the output layers of V1 cortex, neurons in layer 2/3. There isn t really one receptive field for a layer 2/3 neuron but rather different receptive fields for different stimulus ensembles, different contexts. The remarkable thing is that when their receptive fields are mapped with what I have called  sparse noise , layer 2/3 neurons respond selectively to black spots rather than white.

Photoreceptors from archaea, bacteria, and green algae were molecularly identified in recent years. We could show that some of them are ideal tools to manipulate animal cells by illumination. The Channelrhodopsins from the unicellular green alga C. reinhardtii are Light-gated cation channels which allow fast light-induced depolarization1,2 of the plasma membrane. Mutations led to a slower photocycle and therefore to Channelrhodopsins with higher light sensitivity. Neuronal expression of Channelrhodopsin-2 (ChR2) yields Light-induced action potentials and Light-manipulated behaviour3 in C. elegans. The Light-activated chloride pump halorhodopsin (HR) from the archaeum Natronomonas pharaonis hyperpolarizes the plasma membrane and therefore allows Light-induced silencing of neurons4. These two antagonistic rhodopsins may even be expressed in the same cell and still specifically be light-activated with 460 nm for ChR2 and 580 nm for HR. We heterologously express Photoactivated Adenylyl Cyclases (PAC) from Euglena gracilis (5,6) or Beggiatoa spec. (7), flavoproteins which quickly elevate cytoplasmic cyclic AMP by illumination with blue light in cultured cells and in living animals or plants. References: 1: Nagel G., D. Ollig, M. Fuhrmann, S. Kateriya, A.M. Musti, E. Bamberg, P. Hegemann (2002). Channelrhodopsin-1: a light-gated proton channel in green algae. Science 296: 2395-2398 2: Nagel, G, T. Szellas, W. Huhn, S. Kateriya, N. Adeishvili, P. Berthold, D. Ollig, P. Hegemann, E. Bamberg. (2003) Channelrhodopsin-2, a directly Light-gated Cation-selective Membrane Channel. Proc Natl Acad Sci U.S.A. 100:13940-13945 3: Nagel, G., M. Brauner, J.F. Liewald, N. Adeishvili, E. Bamberg, A. Gottschalk (2005) Light-activation of Channelrhodopsin-2 in excitable cells of Caenorhabditis elegans triggers rapid behavioral responses. Current Biology 15(24):2279-84. 4: Zhang F., L.-P. Wang, M. Brauner, J.F. Liewald, K. Kay, N. Watzke, P.G. Wood, E. Bamberg, G. Nagel, A. Gottschalk, and K. Deisseroth (2007) Multimodal fast optical interrogation of neural circuits. Nature 446:633-639 5: Schröder-Lang, S., M. Schwärzel, R. Seifert, T. Strünker, S. Kateriya, J. Looser, M. Watanabe, U. B. Kaupp, P. Hegemann, G. Nagel (2007) Fast manipulation of cellular cAMP level by light in vivo. Nat Methods 4(1):39-42 6: Looser J, Schröder-Lang S, Hegemann P, Nagel G. (2009) Mechanistic insights in light-induced cAMP production by photoactivated adenylyl cyclase alpha (PACalpha). Biol Chem. 390(11):1105-11 7: Stierl M, Stumpf P, Udwari D, Gueta R, Hagedorn R, Losi A, Gärtner W, Petereit L, Efetova M, Schwarzel M, Oertner TG, Nagel G, Hegemann P. (2011) Light-modulation of cellular cAMP by a small bacterial photoactivated adenylyl cyclase, bPAC, of the soil bacterium Beggiatoa. J Biol Chem. 286(2):1181-8

Presynaptic terminals must regulate transmission with fine-tuning of synaptic efficacy via reloading of their synaptic vesicle pools and controlling of the Ca²⁺ channel activity despite encountering wide variations in the number and frequency of incoming action potentials. We have addressed above issue at a model cholinergic synapse formed between superior cervical ganglion neurons. We combined genetic knockdown/overexpression and direct physiological measurements of synaptic transmission from paired neurons to show presynaptic proteins function. Dynamin, an essential endocytic protein, controls the reloading of their synaptic vesicle pools. Three isoforms of dynamin work together to match vesicle reuse-pathways having distinct rate and time constants with physiological AP frequencies. Phosphorylation of CAST, the core protein of the active zone proteins complex, controls the speed of synaptic vesicle reloading to the readily releasable pool shortly after an action potential. Ca²⁺ channel activity is temporally controlled by residual Ca²⁺ through CaMKII and Ca²⁺-sensors which interact with Ca²⁺ channels. Thus, action potential firing conducts multiple actions of presynaptic terminal proteins that play a role in different synaptic vesicle stage, and orchestrates synaptic efficacy.

Neural activity differs from wakefulness to deep sleep. In contrast, a single attractor state, called self-organized critical (SOC), was proposed to govern brain dynamics because it supposedly allows for optimal information processing. But is the human brain SOC for each vigilance state despite the variations in neuronal dynamics? We characterized neuronal avalanches - spatiotemporal waves of enhanced activity - from intracranial depth recordings in humans. We showed that avalanche distributions closely followed a power law - the hallmark feature of SOC systems - for each vigilance state. However, avalanches clearly differed with vigilance states: slow wave sleep showed larger avalanches, wakefulness intermediate, and rapid eye movement (REM) sleep smaller ones. Our SOC model together with the data suggested (1) that these differences were mediated by global but tiny changes in synaptic strength and (2) that the changes with vigilance states reflect transition within the subcritical regime close to criticality. In contrast to criticality, a subcritical regime of operations allows for a more stable mode of operation, and keeps a safety margin to the supercritical regime, which is linked to epilepsy. To back up this study, we analyzed for SOC models how spatial subsampling affects the avalanche distributions. We show that for the above study sampling was sufficiently dense, but we also show that subsampling can heavily distort the observed avalanche distributions. These distortions depend on the number and distance between sampled sites, and can lead to misclassifications of a system. The distortions are also model-specific. This in turn allows to exploit systematic subsampling for model selection in the context of SOC and beyond.

It is well established that perceptual and cognitive processes involve the coordinated activity of large populations of neurons distributed over multiple cortical regions. However, we remain surprisingly ignorant of the spatio-temporal organization of these processes, their underlying neuronal mechanisms, and their relation to behavior. This gap in understanding stems largely from the complex and non-stationary nature of distributed cortical activity and from technical limitations in our ability to make appropriate electrophysiological measurements. In my presentation, I will present new experimental findings, from large-scale, multi-electrode recordings in macaque monkeys, demonstrating content-specific spatiotemporal patterns of coherent activity across the cortical network during visual working memory.