A neuromorphic model of olfactory processing and sparse coding in the Drosophila larva brain

Animal nervous systems are highly efficient in processing sensory input. The neuromorphic computing paradigm aims at the hardware implementation of neural network computations to support novel solutions for building brain-inspired computing systems. Here, we take inspiration from sensory processing in the nervous system of the fruit fly larva. With its strongly limited computational resources of <200 neurons and <1.000 synapses the larval olfactory pathway employs fundamental computations to transform broadly tuned receptor input at the periphery into an energy efficient sparse code in the central brain. We show how this approach allows us to achieve sparse coding and increased separability of stimulus patterns in a spiking neural network, validated with both software simulation and hardware emulation on mixed-signal real-time neuromorphic hardware. We verify that feedback inhibition is the central motif to support sparseness in the spatial domain, across the neuron population, while the combination of spike frequency adaptation and feedback inhibition determines sparseness in the temporal domain. Our experiments demonstrate that such small-sized, biologically realistic neural networks, efficiently implemented on neuromorphic hardware, can achieve parallel processing and efficient encoding of sensory input at full temporal resolution.

Directional reorientation of migrating neutrophils is limited by suppression of receptor input signaling at the cell rear through myosin II activity

To migrate efficiently to target locations, cells must integrate receptor inputs while maintaining polarity: a distinct front that leads and a rear that follows. Here we investigate what is necessary to overwrite pre-existing front-rear polarity in neutrophil-like HL60 cells migrating inside straight microfluidic channels. Using subcellular optogenetic receptor activation, we show that receptor inputs can reorient weakly polarized cells, but the rear of strongly polarized cells is refractory to new inputs. Transient stimulation reveals a multi-step repolarization process, confirming that cell rear sensitivity to receptor input is the primary determinant of large-scale directional reversal. We demonstrate that the RhoA/ROCK/myosin II pathway limits the ability of receptor inputs to signal to Cdc42 and reorient migrating neutrophils. We discover that by tuning the phosphorylation of myosin regulatory light chain we can modulate the activity and localization of myosin II and thus the amenability of the cell rear to ‘listen’ to receptor inputs and respond to directional reprogramming.

A neuromorphic model of olfactory processing and sparse coding in the Drosophila larva brain

Animal nervous systems are highly efficient in processing sensory input. The neuromorphic computing paradigm aims at the hardware implementation of similar mechanism to support novel solutions for building brain-inspired computing systems. Here, we take inspiration from sensory processing in the nervous system of the fruit fly larva. With its strongly limited computational resources of <200 neurons and <1.000 synapses the larval olfactory pathway employs fundamental computations to transform broadly tuned receptor input at the periphery into an energy efficient sparse code in the central brain. We show how this approach allows us to achieve sparse coding and increased separability of stimulus patterns in a spiking neural network, validated with both software simulation and hardware emulation on mixed-signal real-time neuromorphic hardware. We verify that feedback inhibition is the central motif to support sparseness in the spatial domain, across the neuron population, while the combination of spike frequency adaptation and feedback inhibition determines sparseness in the temporal domain. Our experiments demonstrate that such small-sized, biologically realistic neural networks, efficiently implemented on neuromorphic hardware, can achieve parallel processing and efficient encoding of sensory input at full temporal resolution.

Directional reorientation of migrating neutrophils is limited by suppression of receptor input signaling at the cell rear through myosin II activity

ABSTRACTTo migrate efficiently to target locations, cells must integrate receptor inputs while maintaining polarity: a distinct front that leads and a rear that follows. Here we investigate what is necessary to overwrite pre-existing front/rear polarity in neutrophil-like HL60 cells migrating inside straight microfluidic channels. Using subcellular optogenetic receptor activation, we show that receptor inputs can reorient weakly polarized cells, but the rear of strongly polarized cells is refractory to new inputs. Transient stimulation reveals a multi-step repolarization process, confirming that cell rear sensitivity to receptor input is the primary determinant of large-scale directional reversal. We demonstrate that the RhoA/ROCK/myosin II pathway limits the ability of receptor inputs to signal to Cdc42 and reorient migrating neutrophils. We discover that by tuning the phosphorylation of myosin regulatory light chain we can modulate the activity and localization of myosin II and thus the amenability of the cell rear to ‘listen’ to receptor inputs and respond to directional reprogramming.

Quantifying signal persistence in the T cell signaling network using an optically controllable antigen receptor

SUMMARYT cells discriminate between healthy and infected cells with remarkable sensitivity when mounting an immune response. It has been hypothesized that this efficient detection requires combining signals from discrete antigen-presenting cell interactions into a more potent response, requiring T cells to maintain a ‘memory’ of previous encounters. To quantify the magnitude of this phenomenon, we have developed an antigen receptor that is both optically and chemically tunable, providing control over the initiation, duration, and intensity of intracellular T-cell signaling within physiological cell conjugates. We observe very limited persistence within the T cell intracellular network on disruption of receptor input, with signals dissipating entirely in ~15 minutes, and directly confirm that sustained proximal receptor signaling is required to maintain active gene transcription. Our data suggests that T cells are largely incapable of integrating discrete antigen receptor signals but instead simply accumulate the output of gene expression. By engineering optical control in a clinically relevant chimeric antigen receptor, we show that this limited signal persistence can be exploited to increase the activation of primary T cells by ~3-fold by using pulsatile stimulation. Our results are likely to apply more generally to the signaling dynamics of other cellular networks.

Integrating Receptor Signal Inputs That Influence Small Rho GTPase Activation Dynamics at the Immunological Synapse

ABSTRACT The Rho GTPase Cdc42 regulates cytoskeletal changes at the immunological synapse (IS) that are critical to T-cell activation. By imaging fluorescent activity biosensors (Raichu) using fluorescence lifetime imaging microscopy, Cdc42 activation was shown to display kinetics that are conditional on the specific receptor input (through two IS-associated receptors, CD3 and β1 integrin). CD3-triggered Cdc42 activity is dependent on the cyto-2 (NPIY) motif of the β1 integrin cytoplasmic domain. Perturbations of the ezrin-radixin-moesin (ERM) function blocked CD3- and β1-dependent increases in Cdc42 activity. Both IS-associated receptors probably lie on a serial molecular pathway and transduce signals through the ERM-dependent machinery that is responsible for the remodeling and stabilization of the synapse. Cdc42 activity is impaired in β1 integrin-deficient T cells that form conjugates with antigen-presenting cells but is partially restored in the context of an antigen-specific synapse. This restoration of Cdc42 activity is due, at least in part, to the recruitment and activation of β2 integrin.

Tracheal constrictor drive above the apneic threshold in anesthetized dogs

We have previously shown that raising arterial Pco 2 (PaCO2 ) by small increments in dogs ventilated below the apneic threshold (AT) results in almost complete tracheal constriction before the return of phrenic activity (Dickstein JA, Greenberg A, Kruger J, Robicsek A, Silverman J, Sommer L, Sommer D, Volgyesi G, Iscoe S, and Fisher JA. J Appl Physiol 81: 1844–1849, 1996). We hypothesized that, if increasing chemical drive above the AT mediates increasing constrictor drive to tracheal smooth muscle, then pulmonary slowly adapting receptor input should elicit more tracheal dilation below the AT than above. In six methohexital sodium-anesthetized, paralyzed, and ventilated dogs, we measured changes in tracheal diameter in response to step increases in tidal volume (Vt) or respiratory frequency (f) below and above the AT at constant PaCO2 (∼40 and 67 Torr, respectively). Increases in Vt(400–1,200 ml) caused significantly more ( P = 0.005) tracheal dilation below than above AT (7.0 ± 2.2 vs. 2.8 ± 1.0 mm, respectively). In contrast, increases in f (14–22 breaths/min) caused similar ( P = 0.93) tracheal dilations below and above (1.0 ± 1.3 and 1.0 ± 0.8 mm, respectively) AT. The greater effectiveness of dilator stimuli below compared with above the AT is consistent with the hypothesis that drive to tracheal smooth muscle increases even after attainment of maximal constriction. Our results emphasize the importance of controlling Pco 2 with respect to the AT when tracheal smooth muscle tone is experimentally altered.