The nature of the memory trace and its neurocomputational implications

The brain processes underlying cognitive tasks must be very robust. Disruptions such as the destruction of large numbers of neurons, or the impact of alcohol and lack of sleep do not have negative effects except when they occur in an extreme form. This robustness implies that the parameters determining the functioning of networks of individual neurons must have large ranges or there must exist stabilizing mechanisms that keep the functioning of a network within narrow bounds. The simulation of a minimal neuronal architecture necessary to study cognitive tasks is described, which consists of a loop of three cell-assemblies. A crucial factor in this architecture is the critical threshold of a cell-assembly. When activated at a level above the critical threshold, the activation in a cell-assembly is subject to autonomous growth, which leads to an oscillation in the loop. When activated below the critical threshold, excitation gradually extinguishes. In order to circumvent the large parameter space of spiking neurons, a rate-dependent model of neuronal firing was chosen. The resulting parameter space of 12 parameters was explored by means of a genetic algorithm. The ranges of the parameters for which the architecture produced the required oscillations and extinctions, turned out to be relatively narrow. These ranges remained narrow when a stabilizing mechanism, controlling the total amount of activation, was introduced. The architecture thus shows chaotic behaviour. Given the overall stability of the operation of the brain, it can be concluded that there must exist other mechanisms that make the network robust. Three candidate mechanisms are discussed: synaptic scaling, synaptic homeostasis, and the synchronization of neural spikes

A Compositionality Machine Realized by a Hierarchic Architecture of Synfire Chains

The composition of complex behavior is thought to rely on the concurrent and sequential activation of simpler action components, or primitives. Systems of synfire chains have previously been proposed to account for either the simultaneous or the sequential aspects of compositionality; however, the compatibility of the two aspects has so far not been addressed. Moreover, the simultaneous activation of primitives has up until now only been investigated in the context of reactive computations, i.e., the perception of stimuli. In this study we demonstrate how a hierarchical organization of synfire chains is capable of generating both aspects of compositionality for proactive computations such as the generation of complex and ongoing action. To this end, we develop a network model consisting of two layers of synfire chains. Using simple drawing strokes as a visualization of abstract primitives, we map the feed-forward activity of the upper level synfire chains to motion in two-dimensional space. Our model is capable of producing drawing strokes that are combinations of primitive strokes by binding together the corresponding chains. Moreover, when the lower layer of the network is constructed in a closed-loop fashion, drawing strokes are generated sequentially. The generated pattern can be random or deterministic, depending on the connection pattern between the lower level chains. We propose quantitative measures for simultaneity and sequentiality, revealing a wide parameter range in which both aspects are fulfilled. Finally, we investigate the spiking activity of our model to propose candidate signatures of synfire chain computation in measurements of neural activity during action execution

A Model of Late Long-Term Potentiation Simulates Aspects of Memory Maintenance

Late long-term potentiation (L-LTP) appears essential for the formation of long-term memory, with memories at least partly encoded by patterns of strengthened synapses. How memories are preserved for months or years, despite molecular turnover, is not well understood. Ongoing recurrent neuronal activity, during memory recall or during sleep, has been hypothesized to preferentially potentiate strong synapses, preserving memories. This hypothesis has not been evaluated in the context of a mathematical model representing biochemical pathways important for L-LTP. I incorporated ongoing activity into two such models: a reduced model that represents some of the essential biochemical processes, and a more detailed published model. The reduced model represents synaptic tagging and gene induction intuitively, and the detailed model adds activation of essential kinases by Ca. Ongoing activity was modeled as continual brief elevations of [Ca]. In each model, two stable states of synaptic weight resulted. Positive feedback between synaptic weight and the amplitude of ongoing Ca transients underlies this bistability. A tetanic or theta-burst stimulus switches a model synapse from a low weight to a high weight stabilized by ongoing activity. Bistability was robust to parameter variations. Simulations illustrated that prolonged decreased activity reset synapses to low weights, suggesting a plausible forgetting mechanism. However, episodic activity with shorter inactive intervals maintained strong synapses. Both models support experimental predictions. Tests of these predictions are expected to further understanding of how neuronal activity is coupled to maintenance of synaptic strength.Comment: Accepted to PLoS One. 8 figures at en

Neuroendocrine Modulation of Complex Behavior and Physiology in C. elegans

To survive, animals must adapt to a complex and challenging world in a way that is flexible and responsive, while maintaining internal homeostasis. Neuromodulators provide a means to systemically alter behavioral or physiological state based on intrinsic or extrinsic cues, however dysregulated neuroendocrine signaling has negative consequences for fitness and survival. Here I examine neuroendocrine function and dysfunction using the escape response in Caenorhabditis elegans. The RFamide neuropeptide FLP-18 is a co-transmitter with the monoamine tyramine and functions both synergistically and antagonistically to tyramine in coordinating escape behavior. Using behavioral analysis and calcium imaging, I show that FLP-18 functions primarily through the G-protein coupled receptor (GPCR) NPR-5 to increase calcium levels in muscle, enhancing locomotion rate, bending and reversal behavior during the escape response. Furthermore, I examine the relationship between persistent acute stress and resilience using repeated activation of the escape response as a model of neuroendocrine dysregulation. Repeated activation of the escape response shortens lifespan and renders animals more susceptible to thermal, oxidative, and nutritional stress. Tyramine release is necessary and sufficient for this effect and activity of the tyraminergic RIM neurons is differentially regulated by acute versus long-term stressors. Impaired stress resistance requires both the GPCR TYRA-3 in the intestine and intestinal neuropeptide release. Activation of the insulin receptor DAF-2 is downstream of TYRA-3 and inhibits the transcription factors DAF-16/FOXO, SKN-1/Nrf2 and HSF-1, linking monoamine signaling in acute stress to the insulin signaling pathway and impaired resilience to long-term stressors