We first divide the time axis in bins of 200 msec and count the number of neurons firing in that time window and determine the time points where this number exceeds M/2, where M is the number of neurons stimulated at t = 2 sec (M = 40). The time difference between these two transition points is the memory span (Figure ?(Figure33). Figure 3 Raster plot of the working those memory model output. A raster plot of the working memory model output (left panel) illustrates the concept of working memory span. Each line of asterisks is the activity of a single neuron with each asterisks indicating an action … Implementation of receptor pharmacology This subsection describes specifically the implementation of 5-HT and ACh neurotransmission physiology.
Other neuromodulatory processes (dopaminergic (DA), noradrenergic (NE)) are implemented using similar approaches. In general, we assume a linear normalized relationship between receptor activation and biological effect on physiological responses such asXYeff=(XYA-XYC)/XYC, where XYA and XYC are the actual activation levels of receptor X subtype Y (for instance 5-HT6) after treatment (A) and the untreated (healthy) control levels (C). 5-HT6 receptor antagonism increases cortical ACh, DA and NE but not 5-HT with a maximal time-dependent effect of +200-250%; while the area under the curve is maximally increased tenfold [33]. 5-HT6 receptors are predominantly located in subcortical areas [34] and antagonism directly increases K+ mediated ACh release in cortical and hippocampal slice [35].
With regard to subcortical DA activity; acute 5-HT6 receptor antagonism shifts DA firing in VTA from bursts to tonic firing with a maximum decrease of 35% in burst firing, while spontaneous activity of substantia nigra DA neurons increases by 40% after chronic 5-HT6 receptor antagonism [36]. We implemented the effect of 5-HT6 receptors in the cortical working Carfilzomib memory model as an increase in free DA, NE and ACh that impacts activation levels of D1, D2, D4, M1, M2, ??7 nicotinic ACh receptor (nACh-R), ??4??2 nACh-R and ??2A receptors. Let P5HT6 be a freely adjustable coupling parameter that will be fitted using clinical data. Given the actual, 5HT6A, and control, 5HT6C, activation levels of the 5-HT6 receptor, we calculate the effect on DA, NE and ACh receptors as, Dx*=Dx(1+P5HT65HT6A-5HT6C5HT6C) (7) where x = 1,2, or 4 (dopaminergic receptors), Mx*=Mx(1+P5HT65HT6A-5HT6C5HT6C) (8) where x = 1,2 (muscarinic receptors), and Nx*=Nx(1+P5HT65HT6A-5HT6C5HT6C) (9) where x = ??7 or ??4??2 (nicotinic receptors).
Cholinergic physiology is implemented through the M1 receptor and both the ??7 and the ??4??2 nACh-R synapses, although pharmacology at the M2 receptor can play a role at this presynaptic autoreceptor. Their interactions are simulated using the cholinergic (muscarinic) receptor competition more info model.
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