Cholinergic regulation of mood: from basic and clinical studies to emerging therapeutics.

Mood disorders are highly prevalent and are the leading cause of disability worldwide. The neurobiological mechanisms underlying depression remain poorly understood, although theories regarding dysfunction within various neurotransmitter systems have been postulated. Over 50 years ago, clinical studies suggested that increases in central acetylcholine could lead to depressed mood. Evidence has continued to accumulate suggesting that the cholinergic system has a important role in mood regulation. In particular, the finding that the antimuscarinic agent, scopolamine, exerts fast-onset and sustained antidepressant effects in depressed humans has led to a renewal of interest in the cholinergic system as an important player in the neurochemistry of major depression and bipolar disorder. Here, we synthesize current knowledge regarding the modulation of mood by the central cholinergic system, drawing upon studies from human postmortem brain, neuroimaging, and drug challenge investigations, as well as animal model studies. First, we describe an illustrative series of early discoveries which suggest a role for acetylcholine in the pathophysiology of mood disorders. Then, we discuss more recent studies conducted in humans and/or animals which have identified roles for both acetylcholinergic muscarinic and nicotinic receptors in different mood states, and as targets for novel therapies

Large Scale Simulations of Two-Species Annihilation, A+B->0, with Drift

We present results of computer simulations of the diffusion-limited reaction process A+B->0, on the line, under extreme drift conditions, for lattices of up to 2^{27} sites, and where the process proceeds to completion (no particles left). These enormous simulations are made possible by the renormalized reaction-cell method (RRC). Our results allow us to resolve an existing controversy about the rate of growth of domain sizes, and about corrections to scaling of the concentration decay.Comment: 13 pages, RevTeX, Submitted to Physics Letters

Two-Species Annihilation with Drift: A Model with Continuous Concentration-Decay Exponents

We propose a model for diffusion-limited annihilation of two species, $A+B\to A$ or $B$, where the motion of the particles is subject to a drift. For equal initial concentrations of the two species, the density follows a power-law decay for large times. However, the decay exponent varies continuously as a function of the probability of which particle, the hopping one or the target, survives in the reaction. These results suggest that diffusion-limited reactions subject to drift do not fall into a limited number of universality classes.Comment: 10 pages, tex, 3 figures, also available upon reques

Path-Integral Formulation of Stochastic Processes for the Exclusive Particle Systems

We present the systematic formalism to derive the path-integral formulation for the hard-core particle systems far from equilibrium. Writing the master equation for a stochastic process of the system in terms of the annihilation and creation operators with the mixed commutation relations, we find the Kramers-Moyal coefficients for the corresponding Fokker-Planck equation (FPE) and the stochastic differential equation (SDE) is derived by connecting these coefficients in the FPE to those in the SDE. Finally, the SDE is mapped onto the field-theory using the path-integral, giving the field-theoretic action which may be analyzed by the renormalization group method. We apply this formalism to the two-species reaction-diffusion system with the drift, finding a universal decay expoent for the long-time behavior of the average concentration of particles in arbitrary dimensions.Comment: 2 figures, revtex style. Revised version with minor change

Spatial Organization in the Reaction A + B --> inert for Particles with a Drift

We describe the spatial structure of particles in the (one dimensional) two-species annihilation reaction A + B --> 0, where both species have a uniform drift in the same direction and like species have a hard core exclusion. For the case of equal initial concentration, at long times, there are three relevant length scales: the typical distance between similar (neighboring) particles, the typical distance between dissimilar (neighboring) particles, and the typical size of a cluster of one type of particles. These length scales are found to be generically different than that found for particles without a drift.Comment: 10 pp of gzipped uuencoded postscrip

Defect-induced phase transition in the asymmetric simple exclusion process

We reconsider the long-standing question of the critical defect hopping rate $r_c$ in the one-dimensional totally asymmetric exclusion process (TASEP) with a slow bond (defect). For $r< r_c$ a phase separated state is observed due to queuing at the defect site whereas for $r\geq r_c$ the defect site has only local effects on the stationary state of the homogeneous system. Mean-field theory predicts $r_c=1$ (when hopping rates outside the defect bond are equal to 1) but numerical investigations seem to indicate $r_c \approx 0.80(2)$. Here we improve the numerics to show that $r_c > 0.99$ and give strong evidence that indeed $r_c=1$ as predicted by mean-field theory, and anticipated by recent theoretical findings.Comment: 5 pages, 6 Figs, version as accepted by Europhysics Letter

Elevated Hippocampal Cholinergic Neurostimulating Peptide precursor protein (HCNP-pp) mRNA in the amygdala in major depression

The amygdala is innervated by the cholinergic system and is involved in major depressive disorder (MDD). Evidence suggests a hyper-activate cholinergic system in MDD. Hippocampal Cholinergic Neurostimulating Peptide (HCNP) regulates acetylcholine synthesis. The aim of the present work was to investigate expression levels of HCNP-precursor protein (HCNP-pp) mRNA and other cholinergic-related genes in the postmortem amygdala of MDD patients and matched controls (females: N=16 pairs; males: N=12 pairs), and in the mouse unpredictable chronic mild stress (UCMS) model that induced elevated anxiety-/depressive-like behaviors (females: N=6 pairs; males: N=6 pairs). Results indicate an up-regulation of HCNP-pp mRNA in the amygdala of women with MDD (p<0.0001), but not males, and of UCMS-exposed mice (males and females; p=0.037). HCNP-pp protein levels were investigated in the human female cohort, but no difference was found. There were no differences in gene expression of acetylcholinesterase (AChE), muscarinic (mAChRs) or nicotinic receptors (nAChRs) between MDD subjects and controls or UCMS and control mice, except for an up-regulation of AChE in UCMS-exposed mice (males and females; p=0.044). Exploratory analyses revealed a baseline expression difference of cholinergic signaling-related genes between women and men (p<0.0001). In conclusion, elevated amygdala HCNP-pp expression may contribute to mechanisms of MDD in women, potentially independently from regulating the cholinergic system. The differential expression of genes between women and men could also contribute to the increased vulnerability of females to develop MDD.Fil: Bassi, Sabrina Cecilia. University of Pittsburgh; Estados Unidos. Hospital Italiano. Instituto de Ciencias Básicas y Medicina Experimental; ArgentinaFil: Seney, Marianne L.. University of Pittsburgh; Estados UnidosFil: Argibay, Pablo. Hospital Italiano. Instituto de Ciencias Básicas y Medicina Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Sibille, Etienne. University of Pittsburgh; Estados Unidos. University of Toronto; Canad

Kinetics of A+B--->0 with Driven Diffusive Motion

We study the kinetics of two-species annihilation, A+B--->0, when all particles undergo strictly biased motion in the same direction and with an excluded volume repulsion between same species particles. It was recently shown that the density in this system decays as t^{-1/3}, compared to t^{-1/4} density decay in A+B--->0 with isotropic diffusion and either with or without the hard-core repulsion. We suggest a relatively simple explanation for this t^{-1/3} decay based on the Burgers equation. Related properties associated with the asymptotic distribution of reactants can also be accounted for within this Burgers equation description.Comment: 11 pages, plain Tex, 8 figures. Hardcopy of figures available on request from S