Computational modeling of spike generation in serotonergic neurons of the dorsal raphe nucleu

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 ten kinds of voltage dependent ion channels as well as calcium-dependent potassium current. Calcium dynamics includes buffering and pumping. In sections 3-9, each component is considered in detail and parameters estimated from voltage clamp data where possible. In the next two sections simplified versions of some components are employed to explore the effects of various parameters on spiking, using a systematic approach, ending up with the following eleven components: a fast sodium current $I_{Na}$, a delayed rectifier potassium current $I_{KDR}$, a transient potassium current $I_A$, a low-threshold calcium current $I_T$, two high threshold calcium currents $I_L$ and $I_N$, small and large conductance potassium currents $I_{SK}$ and $I_{BK}$, a hyperpolarization-activated cation current $I_H$, a leak current $I_{Leak}$ and intracellular calcium ion concentration $Ca_i$. Attention is focused on the properties usually associated with these neurons, particularly long duration of action potential, pacemaker-like spiking and the ramp-like return to threshold after a spike. In some cases the membrane potential trajectories display doublets or have kinks or notches as have been reported in some experimental studies. The computed time courses of $I_A$ and $I_T$ during the interspike interval support the generally held view of a competition between them in influencing the frequency of spiking. Spontaneous spiking could be obtained with small changes in a few parameters from their values with driven spiking.Comment: The abstract has been truncate

Toward a multiscale modeling framework for understanding serotonergic function

Despite its importance in regulating emotion and mental wellbeing, the complex structure and function of the serotonergic system present formidable challenges toward understanding its mechanisms. In this paper, we review studies investigating the interactions between serotonergic and related brain systems and their behavior at multiple scales, with a focus on biologically-based computational modeling. We first discuss serotonergic intracellular signaling and neuronal excitability, followed by neuronal circuit and systems levels. At each level of organization, we will discuss the experimental work accompanied by related computational modeling work. We then suggest that a multiscale modeling approach that integrates the various levels of neurobiological organization could potentially transform the way we understand the complex functions associated with serotonin

Characterization of buspirone effect on output basal ganglia nuclei in 6-hydroxydopamine lesioned rats with and without long-term levodopa treatment.

221 p.La enfermad de Párkinson es un trastorno neurodegenerativo en el que varios sistemas de neurotransmisión se ven afectados. En los últimos años, numerosas evidencias clínicas y experimentales han demostrado el papel del sistema serotonérgico en el desarrollo y en los síntomas de esta enfermedad así como en las complicaciones motoras derivadas del tratamiento crónico con levodopa, conocidas como discinesias inducidas por levodopa. El objetivo de esta tesis ha sido caracterizar el efecto de la buspirona, un agonista parcial de los receptores serotoninérgicos 5-HT1A, en los principales núcleos de salida de los ganglios basales, la substantia nigra pars reticulata (SNr) y el núcleo entopeduncular (EP) mediante técnicas electrofisiológicas in vivo, un estudio histoquímico para la actividad del citocromo c oxidasa (COX) y estudios inmunohistoquímicos para el receptor 5-HT1A y el transportador de la serotonina (SERT), que fueron realizados en los ganglios basales y el núcleo dorsal del rafe. En este trabajo se ha demostrado que el efecto de la buspirona y el agonista total 5-HT1A, 8-OH-DPAT, sobre la actividad de la SNr y el EP se ve comprometido tras el déficit dopaminérgico, y está prácticamente ausente en la actividad oscilatoria entre estos núcleos y la corteza motora. Sin embargo, estos fármacos pueden normalizar la descarga en ¿burst¿ durante el parkinsonismo. Además, se ha observado un aumento generalizado de la actividad de la COX junto con cambios en la expresión del receptor 5-HT1A y del SERT en las ratas parkinsonianas tratadas o sin tratar con levodopa. Estos resultados sugieren que la actividad ¿burst¿ en modelos experimentales es importante para estudiar el efecto terapéutico de nuevos fármacos antiparkinsonianos y antidiscinéticos

Towards building a more complex view of the lateral geniculate nucleus: Recent advances in understanding its role

The lateral geniculate nucleus (LGN) has often been treated in the past as a linear filter that adds little to retinal processing of visual inputs. Here we review anatomical, neurophysiological, brain imaging, and modeling studies that have in recent years built up a much more complex view of LGN . These include effects related to nonlinear dendritic processing, cortical feedback, synchrony and oscillations across LGN populations, as well as involvement of LGN in higher level cognitive processing. Although recent studies have provided valuable insights into early visual processing including the role of LGN, a unified model of LGN responses to real-world objects has not yet been developed. In the light of recent data, we suggest that the role of LGN deserves more careful consideration in developing models of high-level visual processing