Nonlinear signatures of entangled polymer solutions in active microbead rheology.

We present experimental data and numerical modeling of a nonlinear phenomenon in active magnetic microbead rheology that appears to be common to entangled polymer solutions (EPS). Dynamic experiments in a modest range of magnetic forces show: 1. a short-lived high viscosity plateau, followed by 2. a bead acceleration phase with a sharp drop in apparent viscosity, and 3. a terminal steady state that we show resides on the shear-thinning slope of the steady-state flow curve from cone and plate data. This latter feature implies a new protocol to access the nonlinear steady-state flow curve for many biological EPS only available in microliter-scale volumes. We solve the moment-closure form of the Rolie-Poly kinetic model for EPS hydrodynamics, together with a decoupling approximation that obviates the need for a full 3D flow solver, and show that the model qualitatively reproduces the dynamic experimental sequence above. In this way, we explain the phenomenon in terms of entangled polymer physics, and show how the nonlinear event (acceleration and termination on the shear-thinning response curve) is tunable by the interplay between molecular-scale mechanisms (relaxation via reptation and chain retraction) and magnetic force controls. The experimental conditions mimic movement of cilia tips, bacteria, and sperm in mucus barriers, implying a physiological relevance of the phenomenon, and compelling further development of the fully coupled, 3D flow-microstructure model to achieve quantitative accuracy.

Early maternal separation alters neuropeptide Y concentrations in selected brain regions in adult rats.

Human and animal studies support the involvement of neuropeptide Y (NPY) in the pathophysiology of depression. Thus, hippocampal NPY-LI is decreased in genetic models of depression, the Flinders Sensitive Line and Fawn Hooded rats. Maternal "deprivation" has been identified as one risk factor in the development of psychopathology, including depression in adulthood. In view of these findings we hypothesized that brain NPY may also be decreased in an animal model of early life maternal deprivation. To test this hypothesis, male and female Sprague-Dawley rats were maternally separated (MS) 6 h/day or briefly handled from postnatal day 2 (PN2) to PN6 and from PN9 to PN13. At 12 weeks of age the rats were sacrificed, the brains dissected and NPY-LI measured by radioimmunoassay. MS rats had lower NPY-LI in the hippocampus. NPY-LI was also lower in female compared to male rats in hippocampus. Lastly, NPY-LI was increased in the hypothalamus of both male and female MS rats. These findings support the hypothesis that altered NPY in the limbic region is a common denominator of several models of depression and might be a trait marker of vulnerability to affective disorders.

Changed concentrations of tachykinins and neuropeptide Y in brain of a rat model of depression: lithium treatment normalizes tachykinins.

Lithium's therapeutic mechanism of action is unknown. In lithium-treated normal rats, increased striatal concentrations of neurokinin A (NKA)-like immunoreactivity (LI), substance P (SP-LI) and neuropeptide Y (NPY-LI) have been reported. To investigate whether these effects might be of therapeutic relevance, Flinders Sensitive Line rats (FSL), an animal model of depression, and control Flinders Resistant Line (FRL) rats were during a 6-week period fed chow to which either lithium or vehicle was admixed. Following sacrifice, the peptides were extracted from dissected brain regions and measured by radioimmunoassay. NKA-LI and SP-LI were markedly decreased in striatum and increased in frontal cortex in FSL compared to control FRL animals. Lithium treatment abolished these differences. Basal concentrations of NPY-LI were decreased in hippocampus of FSL rats, but unaffected by lithium. The present study suggests that changed tachykinins and NPY may underlie the characterized depressive-like phenotype of the FSL rats. It is hypothesized that altering tachykinin peptidergic neurotransmission in striatum and frontal cortex constitutes a mechanism of action of lithium and that such a mechanism might be of therapeutic relevance.

Neuropeptide Y in brains of the Flinders Sensitive Line rat, a model of depression. Effects of electroconvulsive stimuli and d-amphetamine on peptide concentrations and locomotion.

Neuropeptide Y (NPY), has been implicated in the pathophysiology of depression and the mechanisms of action of electroconvulsive treatment (ECT). In this series of experiments, we explored whether there are differences between Flinders Sensitive Line (FSL) rats, an animal model of depression, and controls, Flinders Resistant Line (FRL) in (1) baseline brain NPY-LI concentrations, (2) effects of ECS on locomotion and brain neuropeptides, (3) amphetamine effects on behavior, and (4) effects of ECS pretreatment on subsequent effects of amphetamine on behavior. Both strains were divided into two groups, receiving eight ECS or ShamECS. Twenty-four hours after the last session, animals were habituated in activity boxes for 45 min before given d-amphetamine (1.5 mg.kg(-1), subcutaneously) or vehicle. Locomotor activity was then recorded for an additional 45 min. Twenty-four hours later, rats were sacrificed by microwave irradiation, the brains dissected into frontal cortex, occipital cortex, hippocampus, hypothalamus and striatum, and the neuropeptides extracted and measured by radioimmunoassay. No differences between FSL and FRL rats in baseline locomotor activity were found. FSL compared to FRL animals showed a significantly larger locomotion increase following saline and a significantly smaller increase following amphetamine. ECS pretreatment significantly decreased the saline effects on locomotion in the FSL and the amphetamine effects in the FRL rats. 'Baseline' NPY-like immunoreactivity (LI) concentrations were lower in the hippocampus of the 'depressed' rats. ECS increased NPY-LI in frontal cortex, occipital cortex and hippocampus of both strains. The hippocampal NPY-LI increase was significantly larger in the FSL compared to FRL animals.

Neuropeptide Y in male and female brains of Flinders Sensitive Line, a rat model of depression. Effects of electroconvulsive stimuli.

Human and animal studies suggest that neuropeptide Y (NPY), a peptide co-localized and co-released with classical neurotransmitters, is involved in the pathogenesis of affective disorders. In addition, lithium, electroconvulsive treatments (ECT in humans and ECS in rodents) and antidepressants affect NPY in a specific temporal- and brain-region fashion. These results have been obtained on healthy male rats; females and/or "depressed" animals have essentially not been studied. Consequently, we studied brain NPY-like immunoreactivity (-LI) under basal conditions and following a series of ECS in both male and female Flinders Sensitive Line (FSL), an animal model of depression, and their controls, the Flinders Resistant Line (FRL) rats. Furthermore, we examined whether the oestrus cycle affects NPY-LI in these strains. Following sacrifice by focused microwave irradiation, the peptides were extracted from dissected brain regions and measured by radioimmunoassay. Hippocampal NPY-LI in both sexes was significantly lower in the "depressed" FSL compared to the control FRL. ECS increased NPY-LI in both male and female rats in both FSL and FRL strains in hippocampus, frontal cortex and occipital cortex. In the hypothalamus, the increase was found only in the FSL rats. In both FSL and control rats, the basal NPY-LI was lower in the hippocampus of female compared to male rats. NPY-LI did not vary during the different phases of the oestrus cycle. These results suggest that the gender differences are not due to NPY-LI variations during the oestrus. The results are consistent with our hypothesis that NPY plays a role in the pathophysiology of depressive disorders and provide further evidence that one of the modes of ECS action is to elevate NPY in the limbic system. Assumption that gender differences in NPY could explain increased rates of depression in women is speculative, but is in line with the findings in the present study.