Choice selective inhibition drives stability and competition in decision circuits.

During perceptual decision-making, the firing rates of cortical neurons reflect upcoming choices. Recent work showed that excitatory and inhibitory neurons are equally selective for choice. However, the functional consequences of inhibitory choice selectivity in decision-making circuits are unknown. We developed a circuit model of decision-making which accounts for the specificity of inputs to and outputs from inhibitory neurons. We found that selective inhibition expands the space of circuits supporting decision-making, allowing for weaker or stronger recurrent excitation when connected in a competitive or feedback motif. The specificity of inhibitory outputs sets the trade-off between speed and accuracy of decisions by either stabilizing or destabilizing the saddle-point dynamics underlying decisions in the circuit. Recurrent neural networks trained to make decisions display the same dependence on inhibitory specificity and the strength of recurrent excitation. Our results reveal two concurrent roles for selective inhibition in decision-making circuits: stabilizing strongly connected excitatory populations and maximizing competition between oppositely selective populations.

Acetylcholine Mediates Dynamic Switching Between Information Coding Schemes in Neuronal Networks.

Rate coding and phase coding are the two major coding modes seen in the brain. For these two modes, network dynamics must either have a wide distribution of frequencies for rate coding, or a narrow one to achieve stability in phase dynamics for phase coding. Acetylcholine (ACh) is a potent regulator of neural excitability. Acting through the muscarinic receptor, ACh reduces the magnitude of the potassium M-current, a hyperpolarizing current that builds up as neurons fire. The M-current contributes to several excitability features of neurons, becoming a major player in facilitating the transition between Type 1 (integrator) and Type 2 (resonator) excitability. In this paper we argue that this transition enables a dynamic switch between rate coding and phase coding as levels of ACh release change. When a network is in a high ACh state variations in synaptic inputs will lead to a wider distribution of firing rates across the network and this distribution will reflect the network structure or pattern of external input to the network. When ACh is low, network frequencies become narrowly distributed and the structure of a network or pattern of external inputs will be represented through phase relationships between firing neurons. This work provides insights into how modulation of neuronal features influences network dynamics and information processing across brain states.

Resonance with subthreshold oscillatory drive organizes activity and optimizes learning in neural networks.

Network oscillations across and within brain areas are critical for learning and performance of memory tasks. While a large amount of work has focused on the generation of neural oscillations, their effect on neuronal populations' spiking activity and information encoding is less known. Here, we use computational modeling to demonstrate that a shift in resonance responses can interact with oscillating input to ensure that networks of neurons properly encode new information represented in external inputs to the weights of recurrent synaptic connections. Using a neuronal network model, we find that due to an input current-dependent shift in their resonance response, individual neurons in a network will arrange their phases of firing to represent varying strengths of their respective inputs. As networks encode information, neurons fire more synchronously, and this effect limits the extent to which further "learning" (in the form of changes in synaptic strength) can occur. We also demonstrate that sequential patterns of neuronal firing can be accurately stored in the network; these sequences are later reproduced without external input (in the context of subthreshold oscillations) in both the forward and reverse directions (as has been observed following learning in vivo). To test whether a similar mechanism could act in vivo, we show that periodic stimulation of hippocampal neurons coordinates network activity and functional connectivity in a frequency-dependent manner. We conclude that resonance with subthreshold oscillations provides a plausible network-level mechanism to accurately encode and retrieve information without overstrengthening connections between neurons.

Connexin 43 gap junctions contribute to brain endothelial barrier hyperpermeability in familial cerebral cavernous malformations type III by modulating tight junction structure.

Familial cerebral cavernous malformations type III (fCCM3) is a disease of the cerebrovascular system caused by loss-of-function mutations in ccm3 that result in dilated capillary beds that are susceptible to hemorrhage. Before hemorrhage, fCCM3 lesions are characterized by a hyperpermeable blood-brain barrier (BBB), the key pathologic feature of fCCM3. We demonstrate that connexin 43 (Cx43), a gap junction (GJ) protein that is incorporated into the BBB junction complex, is up-regulated in lesions of a murine model of fCCM3. Small interfering RNA-mediated ccm3 knockdown (CCM3KD) in brain endothelial cells in vitro increased Cx43 protein expression, GJ plaque size, GJ intracellular communication (GJIC), and barrier permeability. CCM3KD hyperpermeability was rescued by GAP27, a peptide gap junction and hemichannel inhibitor of Cx43 GJIC. Tight junction (TJ) protein, zonula occludens 1 (ZO-1), accumulated at Cx43 GJs in CCM3KD cells and displayed fragmented staining at TJs. The GAP27-mediated inhibition of Cx43 GJs in CCM3KD cells restored ZO-1 to TJ structures and reduced plaque accumulation at Cx43 GJs. The TJ protein, Claudin-5, was also fragmented at TJs in CCM3KD cells, and GAP27 treatment lengthened TJ-associated fragments and increased Claudin 5-Claudin 5 transinteraction. Overall, we demonstrate that Cx43 GJs are aberrantly increased in fCCM3 and regulate barrier permeability by a TJ-dependent mechanism.-Johnson, A. M., Roach, J. P., Hu, A., Stamatovic, S. M., Zochowski, M. R., Keep, R. F., Andjelkovic, A. V. Connexin 43 gap junctions contribute to brain endothelial barrier hyperpermeability in familial cerebral cavernous malformations type III by modulating tight junction structure.

Memory recall and spike-frequency adaptation.

The brain can reproduce memories from partial data; this ability is critical for memory recall. The process of memory recall has been studied using autoassociative networks such as the Hopfield model. This kind of model reliably converges to stored patterns that contain the memory. However, it is unclear how the behavior is controlled by the brain so that after convergence to one configuration, it can proceed with recognition of another one. In the Hopfield model, this happens only through unrealistic changes of an effective global temperature that destabilizes all stored configurations. Here we show that spike-frequency adaptation (SFA), a common mechanism affecting neuron activation in the brain, can provide state-dependent control of pattern retrieval. We demonstrate this in a Hopfield network modified to include SFA, and also in a model network of biophysical neurons. In both cases, SFA allows for selective stabilization of attractors with different basins of attraction, and also for temporal dynamics of attractor switching that is not possible in standard autoassociative schemes. The dynamics of our models give a plausible account of different sorts of memory retrieval.

Formation and Dynamics of Waves in a Cortical Model of Cholinergic Modulation.

Acetylcholine (ACh) is a regulator of neural excitability and one of the neurochemical substrates of sleep. Amongst the cellular effects induced by cholinergic modulation are a reduction in spike-frequency adaptation (SFA) and a shift in the phase response curve (PRC). We demonstrate in a biophysical model how changes in neural excitability and network structure interact to create three distinct functional regimes: localized asynchronous, traveling asynchronous, and traveling synchronous. Our results qualitatively match those observed experimentally. Cortical activity during slow wave sleep (SWS) differs from that during REM sleep or waking states. During SWS there are traveling patterns of activity in the cortex; in other states stationary patterns occur. Our model is a network composed of Hodgkin-Huxley type neurons with a M-current regulated by ACh. Regulation of ACh level can account for dynamical changes between functional regimes. Reduction of the magnitude of this current recreates the reduction in SFA the shift from a type 2 to a type 1 PRC observed in the presence of ACh. When SFA is minimal (in waking or REM sleep state, high ACh) patterns of activity are localized and easily pinned by network inhomogeneities. When SFA is present (decreasing ACh), traveling waves of activity naturally arise. A further decrease in ACh leads to a high degree of synchrony within traveling waves. We also show that the level of ACh determines how sensitive network activity is to synaptic heterogeneity. These regimes may have a profound functional significance as stationary patterns may play a role in the proper encoding of external input as memory and traveling waves could lead to synaptic regularization, giving unique insights into the role and significance of ACh in determining patterns of cortical activity and functional differences arising from the patterns.

A possible mechanism for redox control of human neuroglobin activity.

Neuroglobin (Ngb) promotes neuron survival under hypoxic/ischemic conditions. In vivo and in vitro assays provide evidence for redox-regulated functioning of Ngb. On the basis of X-ray crystal structures and our MD simulations, a mechanism for redox control of human Ngb (hNgb) activity via the influence of the CD loop on the active site is proposed. We provide evidence that the CD loop undergoes a strand-to-helix transition when the external environment becomes sufficiently oxidizing, and that this CD loop conformational transition causes critical restructuring of the active site. We postulate that the strand-to-helix mechanics of the CD loop allows hNgb to utilize the lability of Cys46/Cys55 disulfide bonding and of the Tyr44/His64/heme propionate interaction network for redox-controlled functioning of hNgb.

Social regulation of electric signal plasticity in male Brachyhypopomus gauderio.

In animal communication, the social context that elicits particular dynamic changes in the signal can provide indirect clues to signal function. Female presence should increase the expression of male signal traits relevant for mate-choice, while male presence should promote the enhancement of traits involved in male-male competition. The electric fish Brachyhypopomus gauderio produces a biphasic electric pulse for electrolocation and communication. Pulse amplitude predicts the signaler's body size while pulse duration predicts circulating androgen levels. Males enhance pulse amplitude and duration when the numbers of males and females increase simultaneously. Here we tested the relative effects of female presence and male presence on male signal enhancement, and whether the size of the male competitor affected this enhancement. We found that male presence drives the enhancement of both pulse amplitude and second phase duration, independently of the size of the male competitor. Female presence induces the enhancement of pulse duration, but not pulse amplitude. These data suggest that males probably attend to information about a competitor's body size coded by pulse amplitude and attend to aggressiveness coded by a competitor's pulse duration, both potential predictors of fight outcome. Females may be primarily concerned about information on reproductive condition coded by pulse duration.