Gating small conductance calcium-activated potassium channels in the thalamic reticular nucleus.

Small conductance calcium-activated potassium (SK) channels are well-known regulators of neuronal excitability. In the thalamic hub, SK2 channels act as pacemakers of thalamic reticular neurons, which play a key role in the thalamocortical circuit. Several disease-linked genes are highly enriched in these neurons, including genes known to be associated with schizophrenia and attentional disorders, which could affect neuronal firing. The present study assessed the effect of pharmacological modulation of SK channels in the firing pattern and intrinsic properties of thalamic reticular neurons by performing whole cell patch clamp recordings in brain slices. Two SK positive allosteric modulators and one negative allosteric modulator were used: CyPPA, NS309, and NS8593, respectively. By acting on the burst afterhyperpolarization (AHP), negative modulation of SK channels resulted in increased action potential (AP) firing, increased burst duration, and decreased intervals between bursts. Conversely, both CyPPA and NS309 increased the afterburst AHP, prolonging the interburst interval, which additionally resulted in reduced AP firing in the case of NS309. Alterations in SK channel activity would be expected to alter functioning of thalamocortical circuits. Targeting SK channels could be promising in treating disorders involving thalamic reticular dysfunction such as psychiatric and neurodevelopmental disorders.

Sex peptide regulates female receptivity through serotoninergic neurons in Drosophila.

The courtship ritual is a dynamic interplay between males and females. Courtship successfully leading to copulation is determined by the intention of both parties which is conveyed by complex action sequences. In Drosophila, the neural mechanisms controlling the female's willingness to mate, or sexual receptivity, have only recently become the focus of investigations. Here, we report that pre-mating sexual receptivity in females requires activity within a subset of serotonergic projection neurons (SPNs), which positively regulate courtship success. Of interest, a male-derived sex peptide, SP, which was transferred to females during copulation acted to inhibit the activity of SPN and suppressed receptivity. Downstream of 5-HT, subsets of 5-HT7 receptor neurons played critical roles in SP-induced suppression of sexual receptivity. Together, our study reveals a complex serotonin signaling system in the central brain of Drosophila which manages the female's desire to mate.

Perspectives on Agmatine Neurotransmission in Acute and Chronic Stressrelated Conditions.

Adaptive responses to stressful stimuli in the environment are believed to restore homeostasis after stressful events. Stress activates the hypothalamic-pituitary-adrenocortical (HPA) axis, which releases glucocorticoids (GCs) into the bloodstream. Recently, agmatine, an endogenous monoamine was discovered to have the potential as a pharmacotherapy for stress. Agmatine is released in response to certain stress conditions, especially those involving GCs, and participates in establishing homeostasis disturbed by stress following GC activation. The therapeutic potential of agmatine for the management of psychological diseases involving stress and depression is promising based on a significant amount of literature. When exogenously applied, agmatine leads to reductions in levels of GCs and counteracts stress-related morphologic, synaptic, and molecular changes. However, the exact mechanism of action by which agmatine modifies the effects resulting from stress hormone secretion is not fully understood. This review aims to present the most possible mechanisms by which agmatine reduces the harmful effects of chronic and acute stress. Several studies suggest chronic stress exposure and repeated corticosteroid treatment lower agmatine levels, contributing to stress-related symptoms. Agmatine acts as an antistress agent by activating mTOR signaling, inhibiting NMDA receptors, suppressing iNOS, and maintaining bodyweight by activating α-2adrenergic receptors. Exogenous administration that restores agmatine levels may provide protection against stress-induced changes by reducing GCs release, stimulating anti-inflammatory processes, and releasing neuroprotective factors, which are not found in all therapies currently being used to treat stress-related disorders. The administration of exogenous agmatine should also be considered a therapeutic element that is capable of triggering a neural protective response that counters the effects of chronic stress. When combined with existing treatment strategies, this may have synergistic beneficial effects.

Estrogen attenuates physical and psychological stress-induced cognitive impairments in ovariectomized rats.

INTRODUCTION: Women are more vulnerable to stress-related disorders than men, which is counterintuitive as female sex hormones, especially estrogen, have been shown to be protective against stress disorders. METHODS: In this study, we investigated whether two different models of stress act differently on ovariectomized (OVX) rats and the impact of estrogen on physical or psychological stress-induced impairments in cognitive-behaviors. Adult female Wistar rats at 21-22 weeks of age were utilized for this investigation. Sham and OVX rats were subjected to physical and psychological stress for 1 hr/day for 7 days, and cognitive performance was assessed using morris water maze (MWM) and passive avoidance (PA) tests. The open field and elevated plus maze tests (EPM) evaluated exploratory and anxiety-like behaviors. RESULTS: In sham and OVX rats, both physical and psychological stressors were associated with an increase in EPM-determined anxiety-like behavior. OVX rats exhibited decreased explorative behavior in comparison with nonstressed sham rats (p < .05). Both physical stress and psychological stress resulted in disrupted spatial cognition as assayed in the MWM (p < .05) and impaired learning and memory as determined by the PA test when the OVX and sham groups were compared with the nonstressed sham group. Estrogen increased explorative behavior, learning and memory (p < .05), and decreased anxiety-like behavior compared with vehicle in OVX rats exposed to either type of stressor. CONCLUSIONS: When taken together, estrogen and both stressors had opposite effects on memory, anxiety, and PA performance in a rat model of menopause, which has important implications for potential protective effects of estrogen in postmenopausal women exposed to chronic stress.

Electrophysiological and inflammatory changes of CA1 area in male rats exposed to acute kidney injury: Neuroprotective effects of erythropoietin.

The high mortality rate associated with acute kidney injury (AKI) is commonly due to progressive, inflammatory multiple organ dysfunction, which often involves neurological complications. The AKI-stimulated mechanisms leading to brain dysfunction are not well understood, which hinders development of new therapeutic avenues to minimize AKI-mediated neural effects. The hippocampal CA1 area is a particularly vulnerable region during AKI but the electrophysiological and inflammatory mechanisms involved in this vulnerability remain largely unknown. Here, we used immunohistochemistry to quantitatively investigate the number of astrocytes expressing glial fibrillary acidic protein (GFAP) as an indicator of inflammation, and whole cell patch clamp to evaluate electrophysiological changes in CA1 at different time points following induction of bilateral renal ischemia (BRI) in male Wistar rats. Further we evaluated the effectiveness of erythropoietin (EPO, 1000 U/kg i.p.) in mitigating BRI-associated changes. Plasma concentrations of blood urea nitrogen (BUN) were significantly enhanced at 24 h, 72 h and 1 week, and creatinine (Cr) was increased at 24 h after reperfusion, which were changes reduced by EPO. BRI led to an increase in CA1 GFAP-positive cells 24 h and 72 h, but not 1 week, after reperfusion, and EPO reversed this effect of BRI at 24 h. Additionally, BRI caused an increase in the peak amplitude and coefficient of variation of CA1 pyramidal neuronal action potentials, which were changes not seen in presence of EPO. When taken together, altered neuronal electrophysiological properties and astrogliosis could contribute to the neurological complications induced by AKI, and EPO offers hope as a potential neuroprotective agent.

Affective dimensions of pain and region -specific involvement of nitric oxide in the development of empathic hyperalgesia.

Empathy for pain depends on the ability to feel, recognize, comprehend and share painful emotional conditions of others. In this study, we investigated the role of NO in a rat model of empathic pain. Pain was socially transferred from the sibling demonstrator (SD) who experienced five formalin injection to the naïve sibling observer (SO) through observation. SO rats received L-NAME (a nonspecific NO synthase inhibitor) or L-arginine (a precursor of NO) prior to observing the SD. Nociception, and concentrations of NO metabolites (NOx) in the serum, left and right hippocampus, prefrontal cortex, and cerebellum were evaluated. Nociceptive responses were significantly increased in the pain-observing groups. NOx levels measured 24 h after the last pain observation using the Griess method, were indicative of NOx concentration decreases and increases in the left hippocampus and cerebellum, respectively. There was an increase in tissue concentration of NOx in cerebellum and prefrontal cortex in both pain and observer groups 7 days after the fifth formalin injection. Our results suggest that NO is involved in development of empathic hyperalgesia, and observation of sibling's pain can change NO metabolites in different brain regions in observer rats.

Hyperexcitability of VTA dopaminergic neurons in male offspring exposed to physical or psychological prenatal stress.

Prenatal stress (PS) exposure leads to cognitive and behavioral alterations in offspring including an increased risk of substance abuse and anxiety disorders. Signalling from dopamine (DA) neurons of the ventral tegmental area (VTA) in the mesoaccumbal and mesocortical pathways plays a vital role in drug dependency and anxiety behavior. To provide further knowledge about the changes in drug seeking behavior and anxiety behaviors in prenatally stressed mice, we conducted ex vivo investigations in VTA brain slices of adult male PS offspring to evaluate the effects of two types of PS (physical vs. psychological) on activity of DA neurons. Elevated plus maze (EPM) was used to assess anxiety-like behaviors and conditioned place preference (CPP) was used to evaluate drug reinforcing effects in mice. An increased anxiety-like behavior and preference to morphine was observed in prenatally stressed mice. PS VTA DA cells exhibited greater Ih current and a higher frequency and amplitude of sEPSCs, which were consistent with a greater degree of pre- or postsynaptic excitability of the VTA. This was confirmed by lower rheobase and lower firing thresholds in PS VTA neurons, as well as increases in spontaneous firing frequency. When taken together, these data suggest that alterations in VTA DA neurons in this mouse model of prenatal stress might be associated with later life alterations in drug seeking and anxiety-like behaviors through their role in mesocortical and mesoaccumbal pathways.

Prenatal Nicotine Exposure in Rodents: Why Are There So Many Variations in Behavioral Outcomes?

INTRODUCTION: The World Health Organization (WHO) reported that smoking cessation rates among women have stagnated in the past decade and estimates that hundreds of millions of women will be smokers in the next decade. Social, environmental, and biological conditions render women more susceptible to nicotine addiction, imposing additional challenges to quit smoking during gestation, which is likely why more than 8% of pregnancies in Europe are associated with smoking. In epidemiological investigations, individuals born from gestational exposure to smoking exhibit a higher risk of development of attention-deficit/hyperactive disorder (ADHD) and liability to drug dependence. Among other teratogenic compounds present in tobacco smoke, nicotine actions during neuronal development could contribute to the observed outcomes as nicotine misleads signaling among progenitor cells during brain development. Several experimental approaches have been developed to address the consequences of prenatal nicotine exposure (PNE) to the brain and behavior but, after four decades of studies, inconsistent data have been reported and the lack of consensus in the field has compromised the hypothesis that gestational nicotine exposure participates in cognitive and emotional behavioral deficits. AIMS: In this review, we discuss the most commonly used PNE models with focus on their advantages and disadvantages, their relative validity, and how the different technical approaches could play a role in the disparate outcomes. RESULTS: We propose methodological considerations, which could improve the translational significance of the PNE models. CONCLUSIONS: Such alterations might be helpful in reconciling experimental findings, as well as leading to development of treatment targets for maladaptive behaviors in those prenatally exposed. IMPLICATIONS: In this article, we have reviewed the advantages and disadvantages of different variables of the commonly used experimental models of PNE. We discuss how variations in the nicotine administration methods, the timing of nicotine exposure, nicotine doses, and species employed could contribute to the disparate findings in outcomes for PNE offspring, both in behavior and neuronal changes. In addition, recent findings suggest consideration of epigenetic effects extending across generations. Finally, we have suggested improvements in the available PNE models that could contribute to the enhancement of their validity, which could assist in the reconciliation of experimental findings.

Acute cocaine exposure elicits rises in calcium in arousal-related laterodorsal tegmental neurons.

Cocaine has strong reinforcing properties, which underlie its high addiction potential. Reinforcement of use of addictive drugs is associated with rises in dopamine (DA) in mesoaccumbal circuitry. Excitatory afferent input to mesoaccumbal circuitry sources from the laterodorsal tegmental nucleus (LDT). Chronic, systemic cocaine exposure has been shown to have cellular effects on LDT cells, but acute actions of local application have never been demonstrated. Using calcium imaging, we show that acute application of cocaine to mouse brain slices induces calcium spiking in cells of the LDT. Spiking was attenuated by tetrodotoxin (TTX) and low calcium solutions, and abolished by prior exhaustion of intracellular calcium stores. Further, DA receptor antagonists reduced these transients, whereas DA induced rises with similar spiking kinetics. Amphetamine, which also results in elevated levels of synaptic DA, but via a different pharmacological action than cocaine, induced calcium spiking with similar profiles. Although large differences in spiking were not noted in an animal model associated with a heightened proclivity of acquiring addiction-related behavior, the prenatal nicotine exposed mouse (PNE), subtle differences in cocaine's effect on calcium spiking were noted, indicative of a reduction in action of cocaine in the LDT associated with exposure to nicotine during gestation. When taken together, our data indicate that acute actions of cocaine do include effects on LDT cells. Considering the role of intracellular calcium in cellular excitability, and of the LDT in addiction circuitry, our data suggest that cocaine effects in this nucleus may contribute to the high addiction potential of this drug.

Anandamide and 2-AG are endogenously present within the laterodorsal tegmental nucleus: Functional implications for a role of eCBs in arousal.

Previously, we presented electrophysiological evidence for presence in mice brain slices of functional cannabinoid type I receptors (CB1Rs) within the laterodorsal tegmentum (LDT), a brain stem nucleus critical in control of arousal and rapid eye movement (REM) sleep. Further, using pharmacological agents, we provided data suggestive of the endogenous presence of cannabinoids (CBs) acting at LDT CB1Rs. However, in those studies, identification of the type(s) of CB ligands endogenously present in the LDT remained outstanding, and this information has not been provided elsewhere. Accordingly, we used the highly-sensitive liquid chromatography/mass spectrometry (LC-MS) method to determine whether N-arachidonoylethanolamide (Anandamide or AEA) and 2-arachidonyl glycerol (2-AG), which are both endogenous CB ligands acting at CB1Rs, are present in the LDT. Mice brain tissue samples of the LDT were assayed using ion trap LC-MS in selected ion monitoring mode. Chromatographic analysis and product-ion MS scans identified presence of the CBs, AEA and 2-AG, from LDT mouse tissue. Data using the LC-MS method show that AEA and 2-AG are endogenously present within the LDT and when coupled with our electrophysiological findings, lead to the suggestion that AEA and 2-AG act at electropharmacologically-demonstrated CB1Rs in this nucleus. Accordingly, AEA and 2-AG likely play a role in processes governed by the LDT, including control of states of cortical gamma band activity seen in alert, aroused states, as well as cortical and motor activity characteristic of REM sleep.

Nicotinic Acetylcholine Receptors in the Pathophysiology of Al zheimer's Disease: The Role of Protein-Protein Interactions in Current and Future Treatment.

Nicotinic acetylcholine receptors (nAChRs) have been pursued for decades as potential molecular targets to treat cognitive dysfunction in Alzheimer's disease (AD) due to their positioning within regions of the brain critical in learning and memory, such as the prefrontal cortex and hippocampus, and their demonstrated role in processes underlying cognition such as synaptic facilitation, and theta and gamma wave activity. Historically, activity at these receptors is facilitated in AD by use of drugs that increase the levels of their endogenous agonist acetylcholine, and more recently nAChR selective ligands have undergone clinical trials. Here we discuss recent findings suggesting that the expression and function of nAChRs in AD may be regulated by direct interactions with specific proteins, including Lynx proteins, NMDA-receptors and the Wnt/ß-catenin pathway, as well as ß-amyloid. The ability of protein interactions to modify nAChR function adds a new level of complexity to cholinergic signaling in the brain that may be specifically altered in AD. It is currently not known to what degree current nAChR ligands affect these interactions, and it is possible that the difference in the clinical effect of nAChR ligands in AD is related to differences in their ability to modulate nAChR protein interactions, rather than their effects on ion flow through the receptors. Drugs designed to target these interactions may thus provide a new avenue for drug development to ameliorate cognitive symptoms in AD. Notably, the development of experimental drugs that specifically modulate these interactions may provide the opportunity to selectively affect those aspects of nAChR function that are affected in AD.