Computational modeling of spike generation in serotonergic neurons of the dorsal raphe nucleus.
Serotonergic neurons of the dorsal raphe nucleus, with their extensive innervation of limbic and higher brain regions and interactions with the endocrine system have important modulatory or regulatory effects on many cognitive, emotional and physiological processes. They have been strongly implicated in responses to stress and in the occurrence of major depressive disorder and other psychiatric disorders. In order to quantify some of these effects, detailed mathematical models of the activity of such cells are required which describe their complex neurochemistry and neurophysiology. We consider here a single-compartment model of these neurons which is capable of describing many of the known features of spike generation, particularly the slow rhythmic pacemaking activity often observed in these cells in a variety of species. Included in the model are 11 kinds of ion channels: a fast sodium current INa, a delayed rectifier potassium current IKDR, a transient potassium current IA, a slow non-inactivating potassium current IM, a low-threshold calcium current IT, two high threshold calcium currents IL and IN, small and large conductance potassium currents ISK and IBK, a hyperpolarization-activated cation current IH and a leak current ILeak. In Sections 3-8, each current type is considered in detail and parameters estimated from voltage clamp data where possible. Three kinds of model are considered for the BK current and two for the leak current. Intracellular calcium ion concentration Cai is an additional component and calcium dynamics along with buffering and pumping is discussed in Section 9. The remainder of the article contains descriptions of computed solutions which reveal both spontaneous and driven spiking with several parameter sets. Attention is focused on the properties usually associated with these neurons, particularly long duration of action potential, steep upslope on the leading edge of spikes, pacemaker-like spiking, long-lasting afterhyperpolarization and the ramp-like return to threshold after a spike. In some cases the membrane potential trajectories display doublets or have humps or notches as have been reported in some experimental studies. The computed time courses of IA and IT during the interspike interval support the generally held view of a competition between them in influencing the frequency of spiking. Spontaneous activity was facilitated by the presence of IH which has been found in these neurons by some investigators. For reasonable sets of parameters spike frequencies between about 0.6Hz and 1.2Hz are obtained, but frequencies as high as 6Hz could be obtained with special parameter choices. Topics investigated and compared with experiment include shoulders, notches, anodal break phenomena, the effects of noradrenergic input, frequency versus current curves, depolarization block, effects of cell size and the effects of IM. The inhibitory effects of activating 5-HT1A autoreceptors are also investigated. There is a considerable discussion of in vitro versus in vivo firing behavior, with focus on the roles of noradrenergic input, corticotropin-releasing factor and orexinergic inputs. Location of cells within the nucleus is probably a major factor, along with the state of the animal.
Max Planck Institute for Mathematics in the Sciences, Inselstr. 22, 04103 Leipzig, Germany; School of Electrical and Electronic Engineering, University of Adelaide, Adelaide, South Australia 5005, Australia. Electronic address: Henry.Tuckwell@Adelaide.edu.au.
Henry C
HC
Tuckwell
Department of Physiology and Pharmacology, State University of New York, Downstate Medical Center, Box 29, 450 Clarkson Avenue, Brooklyn, NY 11203-2098, USA; Program in Neural and Behavioral Science and Robert F. Furchgott Center for Neural and Behavioral Science, State University of New York, Downstate Medical Center, Box 29, 450 Clarkson Avenue, Brooklyn, NY 11203-2098, USA.
Nicholas J
NJ
Penington
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000465:Algorithms; D000818:Animals; D001683:Biological Clocks / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D048429:Cell Size; D003198:Computer Simulation; D065847:Dorsal Raphe Nucleus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D007473:Ion Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008959:Models, Neurological; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D051381:Rats; D011985:Receptors, Serotonin / Q000378:metabolism; D059326:Serotonergic Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D012964:Sodium / Q000378:metabolism; D013997:Time Factors
D007473:Ion Channels; D011985:Receptors, Serotonin; D012964:Sodium; D011188:Potassium; D002118:Calcium
Computational model; Dorsal raphe nucleus; Pacemaking; Serotonergic neurons