Water and Brain Function - Effects of Hydration Status on Neurostimulation with Transcranial Magnetic Stimulation.

INTRODUCTION: Neurostimulation/neurorecording are tools to study, diagnose, and treat neurologic/psychiatric conditions. Both techniques depend on volume conduction between scalp and excitable brain tissue. We examine how neurostimulation with TMS is affected by hydration status, a physiologic variable which can influence the volume of fluid spaces/cells, excitability and cellular/global brain functioning. Compared to dehydration, we expected rehydration to show signs of macroscopic and microscopic volume changes including decreased scalp-cortex distance (brain closer to stimulator) and astrocyte swelling-induced glutamate release. METHODS: Normal healthy adult participants (32, 9 male) had common motor TMS measures taken in a repeated measures design from dehydrated (12-hour overnight fast/thirst) and rehydrated (identical dehydration protocol followed by rehydration with 1 L water in 1 hour) testing days. The target region was left primary motor cortex hand area. Response at the target muscle was recorded with electromyography. Urinalysis confirmed hydration status. RESULTS: Motor hotspot shifted in half of participants. Motor threshold decreased in rehydration, indicating increased excitability. Even after re-dosing/re-localizing TMS to the new threshold/hotspot, rehydration still showed evidence of increased excitability: recruitment curve measures generally shifted upwards and SICF was increased. SICI, LICI, LICF, and CSP were relatively unaffected. The hydration perturbations were mild/subclinical, based on the magnitude/speed and urinalysis. DISCUSSION: Motor TMS measures showed evidence of expected physiologic changes of osmotic challenges. Hydration may be a source of variability affecting techniques dependant on brain volumes/volume conduction. These concepts are important for researchers/clinicians using such techniques or dealing with the wide variety of disease processes involving water balance.

Left anterior supramarginal gyrus activity during tool use action observation after extensive tool use training.

The advanced use of complex tools is considered a primary characteristic of human evolution and technological advancement. However, questions remain regarding whether humans possess unique underlying brain networks that support advanced tool-using abilities. Specifically, previous studies have demonstrated the presence of a structurally and functionally unique region in the left anterior supramarginal gyrus (aSMG), that is consistently active during tool use action observation. This region has been proposed as a primary hub for integrating semantic and technical information to form action plans with tools. However, it is still largely unknown how tool use motor learning affects left aSMG activation or connectivity with other brain regions. To address this, participants with little experience using chopsticks observed an experimenter using chopsticks to perform a novel task while undergoing two functional magnetic resonance imaging (fMRI) scans. Between the scans, participants underwent four weeks of behavioral training where they learned to use chopsticks and achieve proficiency in the observed task. Results demonstrated a significant change in effective connectivity between the left aSMG and the left anterior intraparietal sulcus (aIPS), a region involved in object affordances and planning grasping actions. These findings suggest that during unfamiliar tool use, the left aSMG integrates semantic and technical information to communicate with regions involved with grasp selection, such as the aIPS. This communication then allows appropriate grasps to be planned based on the physical properties of the objects involved and their potential interactions.

A Comparative Study of Body Lice and Bed Bugs Reveals Factors Potentially Involved in Differential Vector Competence for the Relapsing Fever Spirochete Borrelia recurrentis.

Borrelia recurrentis is the causative agent of louse-borne relapsing fever and the only Borrelia species transmitted by an insect rather than a tick vector. While bed bugs (Cimex lectularius L.) are not established vectors of any human pathogens, a recent study reported that they may be competent vectors of B. recurrentis. However, many aspects of infection and transmission remain unclear in this possible secondary vector. Here, we carried out several quantitative laboratory studies to gain a better understanding of the host suitability of bed bugs relative to the established body louse vector as well as the factors that may affect the ability of bed bugs to transmit the pathogen. We fed bed bugs B. recurrentis and estimated the level and duration of infection in the hemolymph using live imaging. We performed quantitative PCR (qPCR) to examine whole-body spirochete levels and the occurrence of vertical transmission to progeny. We also developed an assay to compare the amounts of force required to release infectious hemolymph from recently engorged bed bugs and body lice. Finally, we analyzed humoral antibacterial activity in the hemolymph, hemolymph pH, and hemocyte activity in both insect species. Our results confirm that within 24 h of ingestion, B. recurrentis can penetrate the midgut epithelium of bed bugs and enter the hemolymph, overcoming a major host barrier, as in body lice. Once in the hemolymph, spirochetes remain visible for at least 4 days. Moreover, we show that bed bugs are more physically susceptible to crushing than body lice, suggesting that crushing is a feasible route for the natural dissemination of B. recurrentis from the hemolymph of bed bugs, as for body lice. Nonetheless, our data also indicate that bed bugs are suboptimal hosts for B. recurrentis, as the bacterium does not appear to proliferate to high levels or stably colonize the hemolymph and exhibits pleomorphism in this environment. In particular, our data suggest that hemolymph pH and unique cellular immune responses, rather than humoral effectors, may be involved in limiting spirochete survival in bed bugs. Notably, we document the formation of extracellular DNA traps by bed bug hemocytes for the first time. For these reasons, while bed bugs may be capable of limited transmission given their ecology, vector competence is probably minimal relative to body lice. Additional mechanistic studies of human pathogen infection of bed bugs may provide much-needed insight into the biological factors that restrict their ability to act as vectors and may reveal novel mechanisms of immunity.

Rosiglitazone restores nitric oxide synthase-dependent reactivity of cerebral arterioles in rats exposed to prenatal alcohol.

BACKGROUND: Prenatal exposure to alcohol leads to a greater incidence of many cardiovascular-related diseases, presumably via a mechanism that may involve increased oxidative stress. An agonist of peroxisome proliferator-activated receptor gamma (PPARγ; rosiglitazone) has been shown to suppress alcohol-induced neuroinflammation and oxidative stress. The goal of this study was to determine whether acute and chronic treatment with rosiglitazone could restore or prevent impaired nitric oxide synthase (NOS)-dependent responses of cerebral arterioles in male and female adult (14-16 weeks old) rats exposed to alcohol in utero. METHODS: We fed Sprague-Dawley dams a liquid diet with or without 3% ethanol for the duration of their pregnancy (21-23 days). In the first series of studies, we examined the reactivity of cerebral arterioles to eNOS- (ADP), nNOS-dependent (NMDA), and NOS-independent agonists in male and female adult rats before and during acute (1 hour) topical application of rosiglitazone (1 µM). In a second series of studies, we examined the influence of chronic treatment with rosiglitazone (3 mg/kg/day in drinking water for 2-3 weeks) on the responses of cerebral arterioles in male and female adult rats exposed to alcohol in utero. RESULTS: We found that in utero exposure to alcohol similarly reduced responses of cerebral arterioles to ADP and NMDA, but not to nitroglycerin in male and female adult rats. In addition, acute treatment of the male and female adult rats with rosiglitazone similarly restored this impairment in cerebral vascular function to that observed in controls. We also found that chronic treatment with rosiglitazone prevented impaired vascular function in male and female adult rats that were exposed to alcohol in utero. CONCLUSIONS: PPARγ activation may be an effective and relevant treatment to reverse or prevent cerebral vascular abnormalities associated with prenatal exposure to alcohol.

Engaging Undergraduate Students in Substance Use and Related Mental Health Disorders Research within South Dakota: A Review of the Summer Program for Undergraduate Research in Addiction (SPURA).

BACKGROUND: The Summer Program for Undergraduate Research in Addiction (SPURA) at the University of South Dakota provides research opportunities to better understand substance use and related mental health disorders. The program was initiated in 2014 from funding from the National Institute on Drug Abuse with a mission to provide high-quality mentorship and research experiences for undergraduate students, including those underrepresented in science, technology, engineering, and math. METHODS: Students from the University of South Dakota were recruited to participate in this program. Survey responses and demographic information were collected from the students. RESULTS: During the first five years, 37 students completed the program. Many of these students were underrepresented in science. Of the students that had completed their undergraduate degree at the time of the last survey, most students either continued their education in a health professional or graduate program, or were employed in a career related to mental health or substance use. CONCLUSIONS: The current report reflects upon the outcomes of the program and future directions. With continued effort, SPURA will provide critical education for future leaders and health care professionals on topics related to substance use and mental health disorders, resulting in a greater number of advocates for those afflicted by substance use.

Enhanced dopamine D2 autoreceptor function in the adult prefrontal cortex contributes to dopamine hypoactivity following adolescent social stress.

Adult psychiatric disorders characterized by cognitive deficits reliant on prefrontal cortex (PFC) dopamine are promoted by teenage bullying. Similarly, male Sprague-Dawley rats exposed to social defeat in mid-adolescence (P35-39) show impaired working memory in adulthood (P56-70), along with decreased medial PFC (mPFC) dopamine activity that results in part from increased dopamine transporter-mediated clearance. Here, we determined if dopamine synthesis and D2 autoreceptor-mediated inhibition of dopamine release in the adult mPFC are also enhanced by adolescent defeat to contribute to later dopamine hypofunction. Control and previously defeated rats did not differ in either DOPA accumulation following amino acid decarboxylase inhibition (NSD-1015 100 mg/kg ip.) or total/phosphorylated tyrosine hydroxylase protein expression, suggesting dopamine synthesis in the adult mPFC is not altered by adolescent defeat. However, exposure to adolescent defeat caused greater decreases in extracellular dopamine release (measured using in vivo chronoamperometry) in the adult mPFC upon local infusion of the D2 receptor agonist quinpirole (3 nM), implying greater D2 autoreceptor function. Equally enhanced D2 autoreceptor-mediated inhibition of dopamine release is seen in the adolescent (P40 or P49) mPFC, which declines in control rats by adulthood. However, this developmental decrease in autoreceptor function is absent following adolescent defeat, suggesting retention of an adolescent-like phenotype into adulthood. Current and previous findings indicate adolescent defeat decreases extracellular dopamine availability in the adult mPFC via both enhanced inhibition of dopamine release and increased dopamine clearance, which may be viable targets for improving treatment of cognitive deficits seen in neuropsychiatric disorders promoted by adolescent stress.

Serotonergic responses to stress are enhanced in the central amygdala and inhibited in the ventral hippocampus during amphetamine withdrawal.

Withdrawal from amphetamine increases anxiety and reduces the ability to cope with stress, which are factors that are believed to contribute to drug relapse. Stress-induced serotonergic transmission in the central nucleus of the amygdala is associated with anxiety states and fear. Conversely, stress-induced increases in ventral hippocampal serotonin (5-HT) levels have been linked to coping mechanisms. The goal of this study was to investigate the neurobiological changes induced by amphetamine that contribute to stress sensitivity during withdrawal. We tested the hypothesis that limbic serotonergic responses to restraint stress would be altered in male Sprague-Dawley rats chronically pretreated with amphetamine (2.5 mg/kg, intraperitoneal) and then subjected to 2 weeks of withdrawal. Amphetamine withdrawal resulted in increased stress-induced behavioral arousal relative to control treatment, suggesting that drug withdrawal induced greater sensitivity to the stressor. When microdialysis was used to determine the effects of restraint on extracellular 5-HT, stress-induced increases in 5-HT levels were abolished in the ventral hippocampus and augmented in the central amygdala during amphetamine withdrawal. Reverse dialysis of the glucocorticoid receptor antagonist mifepristone into the ventral hippocampus blocked the stress-induced increase in 5-HT levels in saline-pretreated rats, suggesting that glucocorticoid receptors mediate stress-induced increases in 5-HT levels in the ventral hippocampus. However, mifepristone had no effect on stress-induced increases in 5-HT levels in the central amygdala, indicating that stress increases 5-HT levels in this region independently of glucocorticoid receptors. During amphetamine withdrawal, the absence of stress-induced increases in ventral hippocampal 5-HT levels combined with enhanced stress-induced serotonergic responses in the central amygdala may contribute to drug relapse by decreasing stress-coping ability and heightening stress responsiveness.

Sub-region expression of brain-derived neurotrophic factor in the dorsal hippocampus and amygdala is Affected by mild traumatic brain injury and stress in male rats.

The US population suffers 1.5 million head injuries annually, of which mild traumatic brain injuries (mTBI) comprise 75%. Many individuals subsequently experience long-lasting negative symptoms, including anxiety. Previous rat-based work in our laboratory has shown that mTBI changes neuronal counts in the hippocampus and amygdala, regions associated with anxiety. Specifically, mTBI increased neuronal death in the dorsal CA1 sub-region of the hippocampus, but attenuated it in the medial (MeA) and the basolateral nuclei of the amygdala nine days following injury, which was associated with greater anxiety. We have also shown that glucocorticoid receptor (GR) antagonism prior to concomitant stress and mTBI extinguishes anxiety-like behaviors. Using immunohistochemistry, this study examines the expression of brain-derived neurotrophic factor (BDNF) following social defeat and mTBI, and whether this is affected by prior glucocorticoid receptor antagonism as a potential mechanism behind these anxiety and neuronal differences. Here, stress and mTBI upregulate BDNF in the MeA, and both GR and mineralocorticoid receptor antagonism downregulate BDNF in the dorsal hippocampal CA1 and dentate gyrus, as well as the central nucleus of the amygdala. These findings suggest BDNF plays a role in the mechanism underlying neuronal changes following mTBI in amygdalar and hippocampal subregions, and may participate in stress elicited changes to neural plasticity in these regions. Taken together, these results suggest an essential role for BDNF in the development of anxiety behaviors following concurrent stress and mTBI.

Influence of chronic amphetamine treatment and acute withdrawal on serotonin synthesis and clearance mechanisms in the rat ventral hippocampus.

Amphetamine withdrawal in both humans and rats is associated with increased anxiety states, which are thought to contribute to drug relapse. Serotonin in the ventral hippocampus mediates affective behaviors, and reduced serotonin levels in this region are observed in rat models of high anxiety, including during withdrawal from chronic amphetamine. This goal of this study was to understand the mechanisms by which reduced ventral hippocampus serotonergic neurotransmission occurs during amphetamine withdrawal. Serotonin synthesis (assessed by accumulation of serotonin precursor as a measure of the capacity of in vivo tryptophan hydroxylase activity), expression of serotonergic transporters, and in vivo serotonergic clearance using in vivo microdialysis were assessed in the ventral hippocampus in adult male Sprague Dawley rats at 24 h withdrawal from chronic amphetamine. Overall, results showed that diminished extracellular serotonin at 24 h withdrawal from chronic amphetamine was not accompanied by a change in capacity for serotonin synthesis (in vivo tryptophan hydroxylase activity), or serotonin transporter expression or function in the ventral hippocampus, but instead was associated with increased expression and function of organic cation transporters (low-affinity, high-capacity serotonin transporters). These findings suggest that 24 h withdrawal from chronic amphetamine reduces the availability of extracellular serotonin in the ventral hippocampus by increasing organic cation transporter-mediated serotonin clearance, which may represent a future pharmacological target for reversing anxiety states during drug withdrawal.

TMS Bursts Can Modulate Local and Networks Oscillations During Lower-Limb Movement.

PURPOSE: Lower-limb motor functions involve processing information via both motor and cognitive control networks. Measuring oscillations is a key element in communication within and between cortical networks during high-order motor functions. Increased midfrontal theta oscillations are related to improved lower-limb motor performances in patients with movement disorders. Noninvasive neuromodulation approaches have not been explored extensively to understand the oscillatory mechanism of lower-limb motor functions. This study aims to examine the effects of repetitive transcranial magnetic stimulation on local and network EEG oscillations in healthy elderly subjects. METHODS: Eleven healthy elderly subjects (67-73 years) were recruited via advertisements, and they underwent both active and sham stimulation procedures in a random, counterbalanced design. Transcranial magnetic stimulation bursts (θ-transcranial magnetic stimulation; 4 pulses/second) were applied over the midfrontal lead (vertex) before a GO-Cue pedaling task, and signals were analyzed using time-frequency methods. RESULTS: Transcranial magnetic stimulation bursts increase the theta activity in the local ( p = 0.02) and the associated network during the lower-limb pedaling task ( p = 0.02). Furthermore, after task-related transcranial magnetic stimulation burst sessions, increased resting-state alpha activity was observed in the midfrontal region ( p = 0.01). CONCLUSIONS: This study suggests the ability of midfrontal transcranial magnetic stimulation bursts to directly modulate local and network oscillations in a frequency manner during lower-limb motor task. Transcranial magnetic stimulation burst-induced modulation may provide insights into the functional roles of oscillatory activity during lower-limb movement in normal and disease conditions.

GABAA Receptor and Serotonin Transporter Expression Changes Dissociate Following Mild Traumatic Brain Injury: Influence of Sex and Estrus Cycle Phase in Rats.

Mild traumatic brain injuries (mild TBIs) can affect both males and females, but females are more likely to report long-term psychological complications, including changes in mood and generalized anxiety. Additionally, reproductive cycle phase has been shown to affect mild TBI symptom expression within females. These variances may result from sex differences in mild TBI-induced alterations to neurotransmission in brain regions that influence mood and emotion, possibly mediated by sex steroids. The hippocampus and amygdala are implicated in stress responses and anxiety, and within these regions, gamma-aminobutyric acid (GABA) and serotonin modulate output and behavioral expression. Metabolites of progesterone can allosterically enhance GABAergic signaling, and sex steroids are suggested to regulate the expression of the serotonin transporter (SERT). To determine how mild TBI might alter GABA receptor and SERT expression in males and females, immunocytochemistry was used to quantify expression of the alpha-1 subunit of the GABAA receptor (α1-GABAA), SERT, and a neuronal marker (NeuN) in the brains of adult male and naturally-cycling female rats, both with and without mild TBI, 17 days after injury. Mild TBI altered the expression of α1-GABAA in the amygdala and hippocampus in both sexes, but the direction of change observed depended on sex and reproductive cycle phase. In contrast, mild TBI had little effect on SERT expression. However, SERT expression differed between sexes and varied with the cycle phase. These findings demonstrate that regulation of neurotransmission following mild TBI differs between males and females, with implications for behavioral outcomes and the efficacy of therapeutic strategies.

Chronic administration of glucocorticoid receptor ligands increases anxiety-like behavior and selectively increase serotonin transporters in the ventral hippocampus.

Organic cation transporter-3 (OCT3) is widely distributed in the brain with high expression in portions of the stress axis. These high capacity, polyspecific transporters function in monoamine clearance and are sensitive to the stress hormone corticosterone. In rats, withdrawal from chronic amphetamine increases OCT3 expression in specific limbic brain regions involved anxiety and stress responses, including the ventral hippocampus, central nucleus of amygdala (CeA) and dorsomedial hypothalamus. (DMH). Previous studies show that glucocorticoid receptor (GR) agonists increase OCT1 mRNA and OCT2 mRNA expression in non-neural tissues. Thus, we hypothesized that corticosterone increases OCT3 expression in the brain by activating GRs. Male Sprague-Dawley rats were pre-treated daily with the GR antagonist mifepristone (20 mg/kg; sc.) or vehicle followed 45 min later by injections of corticosterone or vehicle for 2 weeks. Corticosterone treatment significantly increased OCT3 expression in the ventral hippocampus and increased anxiety-like behavior. However, these effects were not blocked by mifepristone. Interestingly, treatment with mifepristone alone reduced plasma corticosterone levels and increased serotonin transporter and GR expression in the ventral hippocampus but did not significantly affect OCT3 expression or behavior. No treatment effects on OCT3, serotonin transporter or GR expression were observed in the DMH, CeA or dorsal hippocampus. Our findings suggest that corticosterone increases OCT3 expression in the ventral hippocampus by a mechanism independent of GRs, and that mifepristone and corticosterone can act in an independent manner to affect HPA axis-related physiological and behavioral parameters.

Sensorimotor control of object manipulation following middle cerebral artery (MCA) stroke.

Methods for assessing the loss of hand function post-stroke examine limited aspects of motor performance and are not sensitive to subtle changes that can cause deficits in everyday object manipulation tasks. Efficiently lifting an object entails a prediction of required forces based on intrinsic features of the object (sensorimotor integration), short-term updates in the forces required to lift objects that are poorly predicted (sensorimotor memory), as well as the ability to modulate distal fingertip forces, which are not measured by existing assessment tools used in clinics for both diagnostic and rehabilitative purposes. The presented research examined these three components of skilled object manipulation in 60 chronic, unilateral middle cerebral artery stroke participants. Performance was compared to age-matched control participants, and linear regressions were used to predict performance based on clinical scores. Most post-stroke participants performed below control levels in at least one of the tasks. Post-stroke participants presented with combinations of deficits in each of the tasks performed, regardless of the hemisphere damaged by the stroke. Surprisingly, the ability to modulate distal forces was impaired in those patients with damage ipsilateral (right hemisphere) to the hand being used. Sensorimotor integration was also impaired in patients with right hemisphere damage, though they performed at control levels in later lifts, whereas left-hemisphere-damaged patients did not. Lastly, during a task requiring sensorimotor memory, neither patient group performed outside of control ranges on initial lifts, with patients with right hemisphere damage showing impaired performance in later lifts suggesting they were unable to learn the mapping novel mapping of color and mass of the objects. The presented research demonstrates unilateral MCA stroke patients can have deficits in one or more components required for the successful manipulation of hand-held objects and that skillful object lifting requires intact bilateral systems. Further, this information may be used in future studies to aid efforts that target rehabilitation regimens to a stroke survivor's specific pattern of deficits.

Sex differences in the effects of mild traumatic brain injury and progesterone treatment on anxiety-like behavior and fear conditioning in rats.

Mild traumatic brain injuries (mild TBIs) commonly occur in young adults of both sexes, oftentimes in high-stress environments. In humans, sex differences have been observed in the development of post-concussive anxiety and PTSD-like behaviors. Progesterone, a sex steroid that has neuroprotective properties, restores cognitive function in animal models following more severe TBI, but its effectiveness in preventing the psychological symptoms associated with mild TBI has not been evaluated. Using a model of mild TBI that pairs a social stressor (social defeat) with weight drop, male and naturally estrous-cycling female rats were treated with 4 mg/kg progesterone or vehicle once daily for 5 days after injury. Behavioral measures, including elevated plus maze (EPM), contextual fear conditioning, and novel object recognition (NOR) were assessed following progesterone treatment. Anxiety-like behavior was increased by mild TBI in male rats, with a smaller effect seen in female rats in the diestrus phase at the time of EPM testing. In contrast, mild TBI impaired fear learning in female rats in estrus at the time of fear acquisition. Progesterone treatment failed to attenuate post-mild TBI anxiety-like behavior in either sex. Furthermore, progesterone increased fear conditioning and impaired NOR discrimination in male rats, independent of TBI status. Overall, both sex and estrous cycle contributed to psychological outcomes following mild TBI, which were not ameliorated by post-TBI progesterone. This suggests sex steroids play an important role as a moderator of the expression of mild TBI-induced psychological symptoms, rather than as a potential treatment for their underlying etiology.

Intranasal Oxytocin and Pain Reduction: Testing a Social Cognitive Mediation Model.

Oxytocin is well known for its role in relationships and social cognition and has more recently been implicated in pain relief and pain perception. Connections between prosocial feelings and pain relief are also well documented; however, the effects of exogenous oxytocin on social cognition and pain have not been explored. The current study tested whether intranasally delivered oxytocin affects pain perception through prosocial behaviors. Additionally, moderation of the effects of oxytocin by life history or genetic polymorphisms is examined. Young adults (n = 43; 65% female) were administered intranasal oxytocin (24 IU) or placebo in a crossover design on two visits separated by a one-week washout period. Pain was delivered via cold pressor. Baseline measures for decision-making and social cognition were collected, as well as pain sensitivity and medication history. Saliva samples were collected for analysis of genetic markers, and urine samples were collected to assess oxytocin saturation. Following oxytocin administration, participants reported increased prosocial cognition and decision-making. Pain perception appeared to be adaptive, with procedural order and expectation affecting perception. Finally, behavioral trust and cooperation responses were significantly predicted by genetic markers. Oxytocin may increase a patient's trust and cooperation and reduce pain sensitivity while having fewer physiological side effects than current pharmaceutical options.

Prenatal exposure to alcohol impairs responses of cerebral arterioles to activation of potassium channels: Role of oxidative stress.

BACKGROUND: Potassium channels play an important role in the basal tone and dilation of cerebral resistance arterioles in response to many stimuli. However, the effect of prenatal alcohol exposure (PAE) on specific potassium channel function remains unknown. The first goal of this study was to determine the influence of PAE on the reactivity of cerebral arterioles to activation of ATP-sensitive potassium (KATP ) and BK channels. Our second goal was to determine whether oxidative stress contributed to potassium channel dysfunction of cerebral arterioles following PAE. METHODS: We fed Sprague-Dawley dams a liquid diet with or without alcohol (3% EtOH) for the duration of their pregnancy (21 to 23 days). We examined in vivo responses of cerebral arterioles in control and PAE male and female offspring (14 to 16 weeks after birth) to activators of potassium channels (Iloprost [BK channels] and pinacidil [KATP channels]), before and following inhibition of oxidative stress with apocynin. RESULTS: We found that PAE impaired dilation of cerebral arterioles in response to activation of potassium channels with iloprost and pinacidil, and this impairment was similar in male and female rats. In addition, treatment with apocynin reversed the impaired vasodilation to iloprost and pinacidil in PAE rats to levels observed in control rats. This effect of apocynin also was similar in male and female rats. CONCLUSIONS: PAE induces dysfunction in the ability of specific potassium channels to dilate cerebral arterioles which appears to be mediated by an increase in oxidative stress. We suggest that these alterations in potassium channel function may contribute to the pathogenesis of cerebral vascular abnormalities and/or behavioral/cognitive deficits observed in fetal alcohol spectrum disorders.

Experimental data exploring the effects of intranasal oxytocin on young adult social preference and attachment to romantic partners, parents, friends, and strangers.

Experimental studies exploring the effects of intranasal oxytocin are typically underpowered due to small samples. Open access to experimental data and procedures and the use of previously employed measures is critical to building more robust and replicable findings, especially in less studied areas of oxytocin research. In this paper, data is provided from a double-blind placebo-controlled crossover study exploring the effects of intranasal oxytocin (IN-OT: 24 IU) on social preference to romantic partners, parents, peers, and strangers. Young adults (N = 44; 91% female) in committed dating relationships completed three phases of data collection including a screening survey followed by two cmd kwdnextpage ?>laboratory visits. In addition to romantic partner-, and stranger attraction ratings, the data is the first to provide comparisons between attachment and social preference ratings to parents, close friends, and romantic partners under placebo and IN-OT conditions. The data also include differences by situational and life history factors known to moderate oxytocin effects. The detailed protocol, and dataflow can be accessed to verify the analysis and findings or to conduct a replication study. The standardized experimental design and common IN-OT protocol add to the capacity for a meta-analysis exploring oxytocin effects on partner preference and may also be directly ported to existing or future studies with related questions to increase sample size and power.

Pre-clinical safety and therapeutic efficacy of a plant-based alkaloid in a human colon cancer xenograft model.

A high-throughput drug screen revealed that veratridine (VTD), a natural plant alkaloid, induces expression of the anti-cancer protein UBXN2A in colon cancer cells. UBXN2A suppresses mortalin, a heat shock protein, with dominant roles in cancer development including epithelial-mesenchymal transition (EMT), cancer cell stemness, drug resistance, and apoptosis. VTD-dependent expression of UBXN2A leads to the deactivation of mortalin in colon cancer cells, making VTD a potential targeted therapy in malignant tumors with high levels of mortalin. VTD was used clinically for the treatment of hypertension in decades past. However, the discovery of newer antihypertensive drugs and concerns over potential neuro- and cardiotoxicity ended the use of VTD for this purpose. The current study aims to determine the safety and efficacy of VTD at doses sufficient to induce UBXN2A expression in a mouse model. A set of flow-cytometry experiments confirmed that VTD induces both early and late apoptosis in a dose-dependent manner. In vivo intraperitoneal (IP) administration of VTD at 0.1 mg/kg every other day (QOD) for 4 weeks effectively induced expression of UBXN2A in the small and large intestines of mice. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays on tissues collected from VTD-treated animals demonstrated VTD concentrations in the low pg/mg range. To address concerns regarding neuro- and cardiotoxicity, a comprehensive set of behavioral and cardiovascular assessments performed on C57BL/6NHsd mice revealed that VTD generates no detectable neurotoxicity or cardiotoxicity in animals receiving 0.1 mg/kg VTD QOD for 30 days. Finally, mouse xenograft experiments in athymic nude mice showed that VTD can suppress tumor growth. The main causes for the failure of experimental oncologic drug candidates are lack of sufficient safety and efficacy. The results achieved in this study support the potential utility of VTD as a safe and efficacious anti-cancer molecule.

Methylation of genes and regulation of inflammatory processes on emotional response in young adults with alcoholic parents.

Many Americans are adult children of an alcoholic parent (ACoA), which can confer an increased risk of trauma and hazardous alcohol use, as well as heritable and environmental genetic influence. Psychological health and related neural activity can be influenced by inflammation responses, but it is not clear how these factors interact regarding risk or resilience to hazardous alcohol use. The goals of this study were to better understand the relationships between current alcohol use and inflammation, how these are modified by single nucleotide polymorphisms (SNPs) and/or epigenetic modifications of inflammation-associated genes; and how these alter neural reactivity to emotionally-salient stimuli. To do so, ACoA participants were dichotomized as resilient (not engaged in hazardous alcohol use) or vulnerable (currently engaged in hazardous alcohol use). Measures of blood-oxygen-level-dependent (BOLD) activity within regions of interest (ROIs), SNPs and DNA methylation of specific inflammation regulatory genes, and biological markers of inflammation were compared between these groups. Vulnerable ACoAs exhibited higher plasma C-reactive protein (CRP) and greater BOLD activity in the right hippocampus and ventral anterior cingulate cortex in response to emotional cues as well as reduced methylation of CRP and glucocorticoid-related genes. Path analysis revealed significant relationships between alcohol use, SNPs, DNA methylation of inflammatory-related genes, CRP levels, and BOLD activity to emotional stimuli. Taken together, these findings suggest a complex association related to hazardous alcohol use in ACoAs that may predict current inflammation and neural reactivity to emotional stimuli. A better understanding of these associations could direct the future of individual treatment options.

I only have eyes for you: Oxytocin administration supports romantic attachment formation through diminished interest in close others and strangers.

Animal studies confirm oxytocin's (OT) role in regulating monogamous sexual behavior in pair-bonding rodents; and human studies are beginning to translate how this highly conserved neuropeptide is implicated in romantic attachment formation. A number of studies have shown how OT promotes relationship exclusivity by diminishing interest in strangers and increasing reward response to partners. Less clear is whether these effects are modulated by romantic duration or life history factors, or if OT's social distancing effects generalize beyond strangers to close relationships. We report the results of a double-blind, placebo-controlled crossover study on the effects of a single dose of intranasal OT (24 IU) on forty-four young adults (91% female) in different stages of romantic attachment formation (M duration=21 months). Participants completed a screening survey and two lab visits separated by 4-weeks, including a diagrammatic measure of attachment to parents and peers, attitudes related to sexual conservatism and partner infidelity, ratings scales of closeness to romantic partners, and visual attractiveness ratings of strangers. Individual differences were examined by life history factors, including maternal love withdrawal and parental separation. Results indicated that OT administration decreased attachment to mothers, decreased attachment to subsidiary attachment figures, and decreased attraction to strangers. In all cases, emotional distancing was stronger among participants in newer romantic relationships. OT increased arousal to partner infidelity and increased sexual conservatism among participants with negative life history experiences (parental separation and high love withdrawal), whereas the reverse was true for participants reporting a more positive life history. Findings suggest that OT supports exclusivity through social distancing from strangers and close others within a sensitive period of attachment formation. In addition, findings indicate OT plays a different role in mate retention strategies by life history.