The peripheral effect of direct current stimulation on brain circuits involving memory

An ongoing debate surrounding transcranial direct current stimulation (tDCS) of the scalp is whether it modulates brain activity both directly and in a regionally constrained manner enough to positively affect symptoms in patients with neurological disorders. One alternative explanation is that direct current stimulation affects neural circuits mainly indirectly, i.e., via peripheral nerves. Here, we report that noninvasive direct current stimulation indirectly affects neural circuits via peripheral nerves. In a series of studies, we show that direct current stimulation can cause activation of the greater occipital nerve (ON-tDCS) and augments memory via the ascending fibers of the occipital nerve to the locus coeruleus, promoting noradrenaline release. This noradrenergic pathway plays a key role in driving hippocampal activity by modifying functional connectivity supporting the consolidation of a memory event.

COMPARATIVE STUDY OF THE ANTINOCICEPTIVE ACTION OF AMITRIPTYLINE WITH FLUOXETINE AND EVALUATION OF THEIR PROBABLE MECHANISM OF THIS ACTION IN ALBINO MICE

Objective: The aim of our study was to compare the anti-nociceptive action of amitriptyline with fluoxetine and evaluation of their probable mechanism of anti-nociceptive action by observing their individual interactions with morphine, naloxone, yohimbine, and ondansetron.Methods: Albino mice weighing 25-35 grams were taken and divided into 12 groups. Group A-Control(distilled water), Group B-amitriptyline 20 mg/kg, Group C-fluoxetine 20 mg/kg, Group D-morphine 5 mg/kg, Group E-amitriptyline 20 mg/kg+ morphine 5 mg/kg, Group F-amitriptyline 20 mg/kg+ naloxone 3 mg/kg, Group G-amitriptyline 20 mg/kg+ yohimbine 2 mg/kg, Group H-amitriptyline 20 mg/kg+ ondansetron 0.1 mg/kg, Group I-fluoxetine 20 mg/kg+morphine 5 mg/kg, Group J-fluoxetine 20 mg/kg+ naloxone 3 mg/kg, Group K-fluoxetine 20 mg/kg+ yohimbine 2 mg/kg and Group L-fluoxetine 20 mg/kg+ ondansetron 0.1 mg/kg. Hot plate method and acetic acid writhing test were used to assess central and peripheral analgesic activity respectively.Results: Both the amitriptyline and fluoxetine-treated animals showed significantly increased reaction time in a hot plate (p<0.05) and a significant decrease in the number of wriths in acetic acid writhing test (p<0.05), when compared with control. Animals in amitriptyline group showed significantly higher reaction time and less number of wriths when compared to fluoxetine group. Morphine increased, while naloxone, yohimbine and ondansetron decreased the reaction time in a hot plate. In the acetic acid writhing test, a number of wriths significantly decreased when co-treated with morphine and increased when co-treated with naloxone, yohimbine and ondansetron.Conclusion: It is concluded that amitriptyline is a better antinociceptive agent than fluoxetine. Their central and peripheral mechanism of antinociception both involve opioidergic, serotonergic and noradrenergic pathway.

Evidence for the Involvement of Monoaminergic Pathways in the Antidepressant-Like Activity of Cymbopogon citratus in Mice

Objectives Depression is a complex neuropsychiatric disorder, which affects the quality of life of the sufferers and treatment approach is associated with serious adverse effects and sometimes therapeutic failures. Cymbopogon citratus leaf (CC) has been reported to exert anti-depressant effect but its mechanism of action is yet to be elucidated hence, the need for this study. Methods The anti-depressant-like effect of Cymbopogon citratus aqueous leaf was evaluated using forced swim test (FST), tail suspension test (TST) and yohimbine-induced lethality test (YLT) in aggregated mice. Interaction studies involving p-chlorophenylalanine (pCPA), an inhibitor of serotonin biosynthesis and yohimbine, α2-adrenergic receptor antagonist were carried out to evaluate the role of monoaminergic system in the anti-depressant-like effect of CC. The effect of CC on spontaneous motor activity (SMA) was also assessed using activity cage. Results Cymbopogon citratus (25 and 50 mg/kg, p.o.) demonstrated antidepressant-like activity devoid of significant stimulation of the SMA in mice. However, the antidepressant-like property of CC was significantly (p<0.05) attenuated by pretreatment with yohimbine suggesting involvement of noradrenergic pathway in the action of the extract. Also, pCPA reversed the anti-immobility effect of CC, indicating the role of serotonergic system in the mediation of its antidepressant activity. Moreover, CC (25 and 50 mg/kg) potentiated the lethal effect of yohimbine in aggregated mice, which further suggest the involvement of monoaminergic systems in its action. Conclusions The results of the study showed that C. citratus might be interacting with serotonergic and noradrenergic pathways to mediate its anti-depressant-like effect in mice.

Neuronal networks and mediators of cortical neurovascular coupling responses in normal and altered brain states

Brain imaging techniques that use vascular signals to map changes in neuronal activity, such as blood oxygenation level-dependent functional magnetic resonance imaging, rely on the spatial and temporal coupling between changes in neurophysiology and haemodynamics, known as ‘neurovascular coupling (NVC)’. Accordingly, NVC responses, mapped by changes in brain haemodynamics, have been validated for different stimuli under physiological conditions. In the cerebral cortex, the networks of excitatory pyramidal cells and inhibitory interneurons generating the changes in neural activity and the key mediators that signal to the vascular unit have been identified for some incoming afferent pathways. The neural circuits recruited by whisker glutamatergic-, basal forebrain cholinergic- or locus coeruleus noradrenergic pathway stimulation were found to be highly specific and discriminative, particularly when comparing the two modulatory systems to the sensory response. However, it is largely unknown whether or not NVC is still reliable when brain states are altered or in disease conditions. This lack of knowledge is surprising since brain imaging is broadly used in humans and, ultimately, in conditions that deviate from baseline brain function. Using the whisker-to-barrel pathway as a model of NVC, we can interrogate the reliability of NVC under enhanced cholinergic or noradrenergic modulation of cortical circuits that alters brain states. This article is part of the themed issue ‘Interpreting BOLD: a dialogue between cognitive and cellular neuroscience’.

Elevated Glucocorticoid Levels Are Responsible for Induction of Tyrosine Hydroxylase mRNA Expression, Phosphorylation, and Enzyme Activity in the Nucleus of the Solitary Tract during Morphine Withdrawal

Chronic opiate exposure induces neurochemical adaptations in the noradrenergic system. Enhanced responsiveness of the hypothalamo-pituitary-adrenal axis after morphine withdrawal has been associated with hyperactivity of ascending noradrenergic input from the nucleus of the solitary tract (NTS-A2) cell group to the hypothalamic paraventricular nucleus (PVN). This study addressed the role of morphine withdrawal-induced corticosterone (CORT) release in regulation of tyrosine hydroxylase (TH), the rate-limiting enzyme of catecholamine biosynthesis in adrenalectomized (ADX) rats supplemented with low CORT pellet (ADX plus CORT). Present results show that in sham-ADX rats, noradrenergic neurons in the NTS-A2 became activated during morphine withdrawal, as indicated by increased TH mRNA expression. However, this induction of TH expression is not detected in ADX plus CORT rats that are unable to mount CORT secretory response to morphine withdrawal. Total TH protein levels were elevated in the NTS-A2 from sham-operated rats during morphine dependence and withdrawal, whereas we did not find any alteration in ADX plus CORT animals. Furthermore, high levels of TH phosphorylated (activated) at Ser31 (but not at Ser40) were found in the A2 area from sham-morphine withdrawn rats. Consistent with these effects, we observed an increase in the enzyme activity of TH in the PVN. However, induction of morphine withdrawal to ADX plus CORT animals did not alter the phosphorylation (activation) of TH in NTS-A2 and decreased TH activity in the PVN. These results suggest the existence of a positive reverberating circle in which elevated glucocorticoids during morphine abstinence play a permissive role in morphine withdrawal-induced activation of noradrenergic pathway innervating the PVN.