Frontiers in Neuroscience

Published by Frontiers

Online ISSN: 1662-453X


Print ISSN: 1662-4548


Figure 1: Regions in the DKT cortical labeling protocol. Cortical regions of interest included in the DKT protocol are displayed on the left hemisphere of the FreeSurfer “fsaverage” average brain template. Top: regions overlaid on lateral (left) and medial (right) views of the inflated cortical surface. The unlabeled area at the center of the medial view corresponds to non-cortical areas along the midline of the prosencephalon. Bottom: regions overlaid on lateral (upper left), medial (upper right), dorsal (lower left), and ventral (lower right) views of the pial surfaces. The surface was automatically labeled with the DKT40 classifier atlas then manually edited as needed. The “fsaverage” data are included in the FreeSurfer distribution in $FREESURFER_HOME/subjects/fsaverage and the DKT-labeled version is available at
Figure 2: Sulci in the DKT protocol. Sulci that form the region boundaries are drawn and labeled on the inflated “fsaverage” left hemisphere lateral (top left), medial (top right), and ventral (bottom) cortical surface. A map of surface curvature is indicated by the red-green colormap. Convex curvature corresponding to gyral crowns are shown in green; concave curvature corresponding to sulcal fundi are shown in red. The masked area at the center of the medial view corresponds to non-cortical areas along the midline of the prosencephalon. “*”, “**”, and “***” indicate the approximate locations of the transverse occipital sulcus, the temporal incisure, and the primary intermediate sulcus, respectively. These landmarks are not clearly distinguishable on the “fsaverage” inflated surface.
Figure 3: Label editing example. A typical manual edit is demonstrated. In the upper left, the pial surface of the right hemisphere is shown with labels generated from the DKT40 classifier atlas. Yellow arrowheads indicate a “double parallel” cingulate sulcus. The atlas failed to extend the rostral and caudal anterior cingulate regions dorso-rostrally to this sulcus, a common error when a parallel cingulate sulcus is present. To correct the error, the rater switches to the inflated surface view (upper right panel), and displays only the region outlines (lower right), which makes the cortical curvature map viewable. The rater then uses the curvature information to draw a line connecting vertices along the fundus of the parallel cingulate sulcus. Additional lines are drawn to subdivide the cingulate gyrus and the new regions are filled and labeled appropriately (bottom left panel). The yellow highlighted outline in the lower right panel indicates the last selected region (rostral anterior cingulate) and the light blue cursor mark within that region indicates the last selected surface vertex.
Table 3 | Sulci included in the DKT labeling protocol and their abbreviations.
Figure 4: Comparison of DK and DKT40 classifier atlases. A comparison of the automatic labeling of the FreeSurfer “fsaverage” cortical surface by the DK and DKT40 atlases. Lateral (upper left), medial (upper right), ventral (lower right), and dorsal (lower left) views of the left hemisphere surface are shown. Regions in color overlaid atop the red-green surface (as in ) indicate areas that were labeled differently by the classifiers; where there are mismatches, the DKT40 labels are shown (with the same colors as in ). Areas denoted by letters mark the approximate location of regions in the DK protocol that were removed in the DKT protocol, including the banks of the superior temporal sulcus (b), frontal pole (f), and temporal pole (t). Additional, relatively large mismatched areas are denoted by numbers. Sources of mismatch between the protocols include: i, differences in region boundaries, particularly for the medial (1) and anterior (2) borders of pars orbitalis, the anterior border of the lateral orbitofrontal region (3), the lateral border of entorhinal cortex (4), and the anterior boundary of lateral orbital gyrus (5), and the posterior boundary of the superior parietal region (6); ii, variability of the bounding landmarks, particularly for the fundus of the parietooccipital sulcus (7) and the inferior frontal sulcus (8); iii, variation in the interpretation of landmarks, particularly for the cingulate sulcus (9), dorso-rostral portion of the circular sulcus (10), the rostral portion of superior frontal sulcus (11), the dorsal portion of the postcentral sulcus (12), the paracentral sulcus (13), and the posterior boundary of the medial and lateral orbitofrontal regions (14), and iv, variation in the training data set that was used to construct the classifier. The medial surface view was rotated from the parasagittal plane to expose the temporal pole.
101 Labeled Brain Images and a Consistent Human Cortical Labeling Protocol
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  • Full-text available

December 2012


9,597 Reads


We introduce the Mindboggle-101 dataset, the largest and most complete set of free, publicly accessible, manually labeled human brain images. To manually label the macroscopic anatomy in magnetic resonance images of 101 healthy participants, we created a new cortical labeling protocol that relies on robust anatomical landmarks and minimal manual edits after initialization with automated labels. The "Desikan-Killiany-Tourville" (DKT) protocol is intended to improve the ease, consistency, and accuracy of labeling human cortical areas. Given how difficult it is to label brains, the Mindboggle-101 dataset is intended to serve as brain atlases for use in labeling other brains, as a normative dataset to establish morphometric variation in a healthy population for comparison against clinical populations, and contribute to the development, training, testing, and evaluation of automated registration and labeling algorithms. To this end, we also introduce benchmarks for the evaluation of such algorithms by comparing our manual labels with labels automatically generated by probabilistic and multi-atlas registration-based approaches. All data and related software and updated information are available on the website.

Neonatal lesions of orbital frontal areas 11/13 in monkeys alter goal-directed behavior but spare fear conditioning and safety signal learning

March 2014


139 Reads

Recent studies in monkeys have demonstrated that damage to the lateral subfields of orbital frontal cortex (OFC areas 11/13) yields profound changes in flexible modulation of goal-directed behaviors and deficits in fear regulation. Yet, little consideration has been placed on its role in emotional and social development throughout life. The current study investigated the effects of neonatal lesions of the OFC on the flexible modulation of goal-directed behaviors and fear responses in monkeys. Infant monkeys received neonatal lesions of OFC areas 11/13 or sham-lesions during the first post-natal week. Modulation of goal-directed behaviors was measured with a devaluation task at 3-4 and 6-7 years. Modulation of fear reactivity by safety signals was assessed with the AX+/BX- fear-potentiated-startle paradigm at 6-7 years. Similar to adult-onset OFC lesions, selective neonatal lesions of OFC areas 11/13 yielded a failure to modulate behavioral responses guided by changes in reward value, but spared the ability to modulate fear responses in the presence of safety signals. These results suggest that these areas play a critical role in the development of behavioral adaptation during goal-directed behaviors, but not or less so, in the development of the ability to process emotionally salient stimuli and to modulate emotional reactivity using environmental contexts, which could be supported by other OFC subfields, such as the most ventromedial subfields (i.e., areas 14/25). Given similar impaired decision-making abilities and spared modulation of fear after both neonatal lesions of either OFC areas 11 and 13 or amygdala (Kazama et al., 2012; Kazama and Bachevalier, 2013), the present results suggest that interactions between these two neural structures play a critical role in the development of behavioral adaptation; an ability essential for the self-regulation of emotion and behavior that assures the maintenance of successful social relationships.

Figure 1: Kinetic model of [11C]acetate metabolism in human brain. [11C]Acetate enters the astrocytes from blood through either carrier-mediated transport (MCT1) or passive diffusion, characterized by the unidirectional clearance K1, [11C]Acetate in the astrocytes either return to blood, characterized by the rate constant k2, or is converted to [11C]acetyl-CoA, thereby entering the tricarboxylic acid (TCA) cycle, where it is joined into amino acids produced from oxaloacetate and α-ketoglutarate, irreversible processes characterized by the rate constant k3, before it is converted to [11C]CO2, which leaves the cell by passive diffusion into the blood, characterized by the rate constant k5.
Figure 2: 11C]acetate PET images. Summed average [11C]-PET images from time of injection of [11C]acetate to 45 min in the groups of patients with cirrhosis and HE (HE), patients with cirrhosis without HE (CL) and healthy subjects (HC), n, number of subjects. Data are presented on a logarithmic scale.
Figure 3: Individual parameter estimates. Patients with cirrhosis and hepatic encephalopathy (HE) (), patients with cirrhosis without HE (), and healthy subjects (). (A) Rate constant of whole brain astrocyte oxidative metabolism, k3vs. unidirectional clearance from blood-to-brain tissue of [11C]acetate, K1. (B) Rate constant for return of [11C]acetate from the astrocytes to blood, k2 vs. K1. (C) Passive diffusion of [11C]CO2 from the astrocytes into the blood, k5 vs. K1. (D) Apparent distribution volume in vascular space, V0 vs. K1. Solid line indicates a tendency.
Figure 4: Predicted time-activity curves for three whole-brain model configurations. (A) Average data sets for patients with cirrhosis and hepatic encephalopathy (HE). (B) Patients with cirrhosis without HE. (C) Healthy subjects. Each panel shows the observed values, the fitted values using a K1k2k3k5V0 model (“full” model), and the predicted behaviors of the K1k2k3V0 and K1k2V0 models. K1, unidirectional clearance from blood-to-brain tissue of [11C]acetate. k2, rate constant for return of [11C]acetate from the astrocytes to blood. k3, rate constant of whole brain astrocyte oxidative metabolism. k5, passive diffusion of [11C]O2 from the astrocytes into the blood. V0, apparent distribution volume in vascular compartment.
Figure 5: Net metabolic clearance and unidirectional clearance from blood-to-brain tissue of [11C]acetate vs. arterial blood ammonia, unidirectional clearance of H2[15O] and cerebral metabolic rate of oxygen. Patients with cirrhosis and hepatic encephalopathy (HE) (), patients with cirrhosis without HE (), and healthy subjects (). (A) Net metabolic clearance of [11C]acetate, K vs. arterial blood ammonia concentration (the latter from Iversen et al., 2009). (B) Net metabolic clearance of [11C]acetate, K vs. cerebral metabolic rate of oxygen, CMRO2 (the latter from Iversen et al., 2009). (C) Unidirectional clearance from blood-to-brain tissue of [11C]acetate, K1 vs. that K1 of H2[15O] (the latter from Iversen et al., 2009); the straight line shows line of identity. Solid line indicates a tendency.
Oxidative metabolism of astrocytes is not reduced in hepatic encephalopathy: A PET study with [11C]acetate in humans

November 2014


253 Reads






In patients with impaired liver function and hepatic encephalopathy (HE), consistent elevations of blood ammonia concentration suggest a crucial role in the pathogenesis of HE. Ammonia and acetate are metabolized in brain both primarily in astrocytes. Here, we used dynamic [(11)C]acetate PET of the brain to measure the contribution of astrocytes to the previously observed reduction of brain oxidative metabolism in patients with liver cirrhosis and HE, compared to patients with cirrhosis without HE, and to healthy subjects. We used a new kinetic model to estimate uptake from blood to astrocytes and astrocyte metabolism of [(11)C]acetate. No significant differences of the rate constant of oxidation of [(11)C]acetate (k 3) were found among the three groups of subjects. The net metabolic clearance of [(11)C]acetate from blood was lower in the group of patients with cirrhosis and HE than in the group of healthy subjects (P < 0.05), which we interpret to be an effect of reduced cerebral blood flow rather than a reflection of low [(11)C]acetate metabolism. We conclude that the characteristic decline of whole-brain oxidative metabolism in patients with cirrhosis with HE is not due to malfunction of oxidative metabolism in astrocytes. Thus, the observed decline of brain oxidative metabolism implicates changes of neurons and their energy turnover in patients with HE.

Repeated measures analysis shows a significant interaction between treatment (OT/placebo) and emotional facial expression (fear/happiness), indicating a differential effect of OT and placebo treatments on recognition of fearful facial expressions, as opposed to happy expressions for all participants. Separate repeated ANOVA indicated significant treatment effect only for fear recognition (*), but not for the recognition of happiness (*p < 0.05).
Separate paired t-tests reveal that participants whose basic fear recognition ability was below the median were significantly improved in fear recognition following OT administration, as opposed to their performance following placebo administration (**). Conversely, participants whose basic fear recognition ability was above the median did not exhibit any significant difference between their OT performance and placebo performance (**p < 0.0001).
Fischer-Shofty M, Shamay-Tsoory SG, Levkovitz Y. Characterization of the effects of oxytocin on fear recognition in patients with schizophrenia and in healthy controls. Frontiers in Neuroscience 7: 127

July 2013


184 Reads

Individuals who suffer from schizophrenia often show a marked deficit in recognition of emotional facial expressions, as part of broader impairment of social cognition. Research has shown that recognition of negative emotions, specifically fear recognition, is particularly impaired among patients with schizophrenia. Recently we reported that intranasal administration of OT (IN OT) increased the ability to correctly recognize fear in a group of healthy men. The aim of the current study was to examine the effects of IN OT administration on fear recognition among patients with schizophrenia. Based on previous research, we also sought to examine a possible selective effect of OT dependent on baseline performance, hypothesizing that IN OT would have a greater enhancement effect on less proficient individuals. It was thus hypothesized that patients will show more improvement in fear recognition following the administration of IN OT as compared to controls. Sixty six participants (31 schizophrenia patients, 35 healthy controls) were enrolled in the current study. All participants received treatment of a single dose of 24 IU IN OT and an equivalent amount of placebo, 1 week apart. The participants' ability to accurately recognize fear and happiness was evaluated using a face morphing task. Overall, as a group, both patients and healthy control participants were more accurate in recognizing fearful facial expressions, but not happy faces, following IN OT administration, as compared to their performance following placebo. IN OT did not differentially affect emotion recognition in patients and healthy controls. Yet, the results indicated a selective effect for IN OT, in which the hormone improves fear recognition only among individuals whose baseline performance was below the median, regardless of their psychiatric status.

Figure 1: Schematic overview of the various stages of adolescence in rats. To model the effects of cannabinoid exposure at different developmental stages, rats can be treated chronically throughout the entire adolescent period (from PND28 through PND61) or during specific stages of adolescence, including early adolescence (beginning at PND28), mid-adolescence (beginning at PND38), or late adolescence (beginning at PND49). The long-term effects of adolescent cannabinoid exposure can then be measured in adulthood. PND, postnatal day.
Renard J, Krebs M-O, Pen Le G, Jay TM. Long-term consequences of adolescent cannabinoid exposure in adult psychopathology. Front Neurosci 8: 1-14

November 2014


380 Reads

Marijuana is the most widely used illicit drug among adolescents and young adults. Unique cognitive, emotional, and social changes occur during this critical period of development from childhood into adulthood. The adolescent brain is in a state of transition and differs from the adult brain with respect to both anatomy (e.g., neuronal connections and morphology) and neurochemistry (e.g., dopamine, GABA, and glutamate). These changes are thought to support the emergence of adult cerebral processes and behaviors. The endocannabinoid system plays an important role in development by acting on synaptic plasticity, neuronal cell proliferation, migration, and differentiation. Delta-9-tetrahydrocanabinol (THC), the principal psychoactive component in marijuana, acts as a partial agonist of the cannabinoid type 1 receptor (CB1R). Thus, over-activation of the endocannabinoid system by chronic exposure to CB1R agonists (e.g., THC, CP-55,940, and WIN55,212-2) during adolescence can dramatically alter brain maturation and cause long-lasting neurobiological changes that ultimately affect the function and behavior of the adult brain. Indeed, emerging evidence from both human and animal studies demonstrates that early-onset marijuana use has long-lasting consequences on cognition; moreover, in humans, this use is associated with a two-fold increase in the risk of developing a psychotic disorder. Here, we review the relationship between cannabinoid exposure during adolescence and the increased risk of neuropsychiatric disorders, focusing on both clinical and animal studies.

Figure 1: Effect of GLP-1 on food intake and associated behaviors is neuroanatomicaly distributed. Local application of GLP-1 or GLP-1 analogs (e.g., EX4) into the VTA or the NAc alters food motivation/reward. Moreover, many other GLP-1R expressing CNS sites that directly respond to GLP-1 have clear connections to the mesolimbic dopamine circuitry, key in food reward behaviors (indicated in blue). This neuroanatomical distribution of GLP-1R potentially allows for a multi-center, wide-spread impact of GLP-1on food reward behavior, at several levels of the CNS. Furthermore, it appears that GLP-1 influences feeding in different brain regions by partly overlapping and partly distinct mechanisms. Several GLP-1 terminal sites have been confirmed (in red). Notably two of them are mesolimbic; VTA and NAc. Presumably, however, most GLP-1R expressing sites would receive their GLP-1 supply from the only source of GLP-1 in the brain, the hindbrain NTS GLP-1-producing neurons. This neuroanatomical architecture places the GLP-1 system as a central sensor of an array of key circulating factors and neural inputs from the viscera and tongue that is immediately able to integrate and relay the information to the mesolimbic centers. Prefrontal cortex, PFC; nucleus tractus solitarius, NTS; ventral tegmental area, VTA; paraventricular nucleus of the hypothalamus, PVH; lateral hypothalamus, LH; arcuate nucleus of the hypothalamus, ARC; ventromedial nucleus of the hypothalamus, VMH; dorsomedial nucleus of the hypothalamus, DMH; conditioned taste aversion, CTA.
Skibicka KP. The central GLP-1: implications for food and drug reward. Front Neurosci 7: 181
Glucagon-like-peptide-1 (GLP-1) and its long acting analogs comprise a novel class of type 2 diabetes (T2D) treatment. What makes them unique among other T2D drugs is their concurrent ability to reduce food intake, a great benefit considering the frequent comorbidity of T2D and obesity. The precise neural site of action underlying this beneficial effect is vigorously researched. In accordance with the classical model of food intake control GLP-1 action on feeding has been primarily ascribed to receptor populations in the hypothalamus and the hindbrain. In contrast to this common view, relevant GLP-1 receptor populations are distributed more widely, with a prominent mesolimbic complement emerging. The physiological relevance of the mesolimbic GLP-1 is suggested by the demonstration that similar anorexic effects can be obtained by independent stimulation of the mesolimbic and hypothalamic GLP-1 receptors (GLP-1R). Results reviewed here support the idea that mesolimbic GLP-1R are sufficient to reduce hunger-driven feeding, the hedonic value of food and food-motivation. In parallel, emerging evidence suggests that the range of action of GLP-1 on reward behavior is not limited to food-derived reward but extends to cocaine, amphetamine, and alcohol reward. The new discoveries concerning GLP-1 action on the mesolimbic reward system significantly extend the potential therapeutic range of this drug target.

Figure 1: Schematic representation of human glucocorticoid receptor gene (NR3C1) non-coding first exons according to Turner and Muller (2005), Sinclair et al. (2012), Steiger et al. (2013). The solid black line boxes with a number represent the different exons and the 5′–3′ orientation goes from left to right. The NR3C1 gene 5′ region is composed of multiple first exons: four in the distal promoter region (A1–3 and I) and ten (D, J, E, B, F, G, C1–3, and H) in the proximal promoter region located in a C—phosphate—G (CpG) island. The exon 1F promoter (lower case) and exon 1F sequence (uppercase) is illustrated. The numbering is relative to the start codon (ATG: +1), which is located 13 nucleotides downstream from the start of exon 2. The 47 CpG sites are in red and numbered. Boxes represent known or putative canonical (solid-lined box) and non-canonical (broken-lined box) NGFI-A–binding sites according to McGowan et al. (2009).
Figure 2: Overview of 16 studies that examined methylation in the exon 1F promoter and exon 1F region of the glucocorticoid receptor gene (NR3C1), and reported methylation changes in specific C—phosphate—G dinucleotides (i.e., CpG sites) in relation to adverse life experiences (occurring in utero or early postnatal life) or conditions associated with adversity: borderline personality disorder (BPD), major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). The 47 CpG sites in the exon 1F promoter (sites 1–43) and exon 1F (sites 44–47) regions are numbered according to , while 12 sites upstream or 5 sites downstream of the region are not numbered. The coverage of every study is represented with a gray box and the direction of the site-specific findings is also depicted (▴ for hypermethylation, ▾ for hypomethylation, ▴▾ for both hyper- and hypo- methylation). The sex distribution, age group of participant at assessment and type of collected tissue are indicated in the left, while the method of quantitative methylation analysis used is indicated on the right. * Denotes the two studies (Perroud et al., 2014b and Martin-Blanco et al., 2014) that were included twice in this overview because they contained site-specific methylation data based on both adverse life experiences and adversity-related conditions.
Figure 3: Percent methylation at each of 39 C-phosphate-G dinucleotides (i.e., CpG sites) of the glucocorticoid receptor gene (NR3C1) exon 1F promoter (sites 6–43) and exon 1F region (site 44) analyzed by cytosine methylation bisulfite mapping (clone-based Sanger sequencing) using peripheral blood mononuclear cells (PBMCs) DNA, in a population of offspring described in our previous publications (Lehrner et al., 2014; Yehuda et al., 2014a). The 39 CpG sites accessed in the study are numbered as in  The represented data (mean ± s.e.m.) are based on a multivariate Two-Way analysis of covariance with maternal and paternal post-traumatic stress disorder (PTSD) as fixed factors and parental Holocaust exposure, age, smoking history, and PBMC-type as covariates. μ, significant maternal PTSD effect. π, significant paternal PTSD effect. x, significant maternal by paternal PTSD interaction effect. Significance was set at p < 0.05. Boxes represent the location of known or putative canonical (solid-lined box) and non-canonical (broken-lined box) NGFI-A binding sites, according to McGowan et al. (2009), and a gray box represents the location of the beginning of exon 1F.
Site-specific methylation changes in the glucocorticoid receptor exon 1F promoter in relation to life adversity: Systematic Review of contributing factors

November 2014


730 Reads

There has been recent interest in epigenetics in psychiatry since it offers a means of understanding how stressful life experiences, in interaction with the genotype, result in epigenetic changes that result in altered gene expression, ultimately affecting the risk for mental disorders. Many studies focused on methylation of the glucocorticoid receptor exon 1F promoter following an initial observation that changes in this region could be modulated by the environment. This review examines all published studies that have attempted to measure methylation in this region using different techniques, several tissue types, populations at different behavioral state and stages of development. Methodological issues have been raised with the aim of attempting to understand methylation quantification and site of action. We propose that it is useful to examine whether methylation at specific sites within the promoter region may be particularly relevant to psychiatric vulnerability to stress-related outcomes.

Table 3 | Serum MIF and PrP C in Control v Mexico City children. 
Brain immune interactions and air pollution: macrophage inhibitory factor (MIF), prion cellular protein (PrPC), Interleukin-6 (IL-6), interleukin 1 receptor antagonist (IL-1Ra), and interleukin-2 (IL-2) in cerebrospinal fluid and MIF in serum differentiate urban children exposed to severe vs. low air pollution

October 2013


358 Reads

Mexico City Metropolitan Area children chronically exposed to high concentrations of air pollutants exhibit an early brain imbalance in genes involved in oxidative stress, inflammation, innate and adaptive immune responses along with accumulation of misfolded proteins observed in the early stages of Alzheimer and Parkinson's diseases. A complex modulation of serum cytokines and chemokines influences children's brain structural and gray/white matter volumetric responses to air pollution. The search for biomarkers associating systemic and CNS inflammation to brain growth and cognitive deficits in the short term and neurodegeneration in the long-term is our principal aim. We explored and compared a profile of cytokines, chemokines (Multiplexing LASER Bead Technology) and Cellular prion protein (PrPC) in normal cerebro-spinal-fluid (CSF) of urban children with high vs. low air pollution exposures. PrPC and macrophage inhibitory factor (MIF) were also measured in serum. Samples from 139 children ages 11.91 ± 4.2 years were measured. Highly exposed children exhibited significant increases in CSF MIF (p = 0.002), IL6 (p = 0.006), IL1ra (p = 0.014), IL-2 (p = 0.04), and PrPC (p = 0.039) vs. controls. MIF serum concentrations were higher in exposed children (p = 0.009). Our results suggest CSF as a MIF, IL6, IL1Ra, IL-2, and PrPC compartment that can possibly differentiate air pollution exposures in children. MIF, a key neuro-immune mediator, is a potential biomarker bridge to identify children with CNS inflammation. Fine tuning of immune-to-brain communication is crucial to neural networks appropriate functioning, thus the short and long term effects of systemic inflammation and dysregulated neural immune responses are of deep concern for millions of exposed children. Defining the linkage and the health consequences of the brain / immune system interactions in the developing brain chronically exposed to air pollutants ought to be of pressing importance for public health.

Inflammasome-IL-1β Signaling Mediates Ethanol Inhibition of Hippocampal Neurogenesis

May 2012


149 Reads

Regulation of hippocampal neurogenesis is poorly understood, but appears to contribute to mood and cognition. Ethanol and neuroinflammation are known to reduce neurogenesis. We have found that ethanol induces neuroinflammation supporting the hypothesis that ethanol induction of neuroinflammation contributes to ethanol inhibition of neurogenesis. To identify the key proinflammatory molecule that may be responsible for ethanol-impaired neurogenesis we used an ex vivo model of organotypic hippocampal-entorhinal cortex brain slice cultures. Here, we demonstrated a key role of proinflammatory cytokine IL-1β signaling in mediating ethanol inhibition of neurogenesis. Ethanol inhibition of neurogenesis was reversed by neutralizing antibody to IL-1β or blockade of the IL-1β receptor with antagonist IL-1RIa. Ethanol-impaired neurogenesis is associated with strong induction of IL-1β and inflammasome proteins NALP1 and NALP3 in both neurons and astrocytes. Blockade of IL-1β synthesis with inflammasome inhibitors Parthenolide and Bay11708 significantly reversed ethanol inhibited neurogenesis. Furthermore, we also found that IL-1β and inflammasome proteins NALP1 and NALP3 are increased in hippocampal neurons and astrocytes in postmortem alcoholic human brain. Together, these novel findings demonstrate that targeting inflammasome-IL-1β signaling can normalize ethanol-impaired hippocampal neurogenesis, which may have therapeutic implications for treatment of cognitive impairment associated with hippocampal dysfunction in alcoholics.

Figure 1: Theories of dopamine and instrumental behavior. Schematic showing (A) basic outline of instrumental, stimulus-response learning three hypothesis on the role of dopamine: (B) anhedonia hypothesis, (C) reinforcement learning hypothesis, and (D) incentive-salience hypothesis.
Figure 2: Mapping formal parameters of reinforcement learning models onto instrumental, stimulus-response learning. (Top) Simplified depiction of cortico-basal ganglia-thalamo-cortical circuits believed to modulate cortical activity and action selection, representing a pathway by which striatum-based reinforcement learning influences behavior. (Bottom) A schematic showing the two key parameters of temporal difference models within a simple stimulus-response diagram. The light red box labeled “associative value” represents the synaptic strength, construed as “value” in computational models, linking a particular stimulus with a particular response. The learning rate reflects dopamine’s modulation of synaptic plasticity, regulating the degree to which outcomes alter learned values (represented by thickness of black arrows). The explore-exploit parameter reflects the degree to which an established value biases the subsequent response (again represented by arrow thickness), reflecting dopamine’s modulation of responsiveness of striatal projection neurons to afferent activity (i.e., a gain mechanism).
Figure 3: Tonic dopamine and the balance between exploration and exploitation. Schematic of hypothesized role of tonic dopamine in mediating thrift in energy expenditure and reward pursuit through regulating the degree to which prior reward learning and value biases behavioral choice.
Thorndike's Law 2.0: Dopamine and the Regulation of Thrift

August 2012


934 Reads

Dopamine is widely associated with reward, motivation, and reinforcement learning. Research on dopamine has emphasized its contribution to compulsive behaviors, such as addiction and overeating, with less examination of its potential role in behavioral flexibility in normal, non-pathological states. In the study reviewed here, we investigated the effect of increased tonic dopamine in a two-lever homecage operant paradigm where the relative value of the levers was dynamic, requiring the mice to constantly monitor reward outcome and adapt their behavior. The data were fit to a temporal difference learning model that showed that mice with elevated dopamine exhibited less coupling between reward history and behavioral choice. This work suggests a way to integrate motivational and learning theories of dopamine into a single formal model where tonic dopamine regulates the expression of prior reward learning by controlling the degree to which learned reward values bias behavioral choice. Here I place these results in a broader context of dopamine's role in instrumental learning and suggest a novel hypothesis that tonic dopamine regulates thrift, the degree to which an animal needs to exploit its prior reward learning to maximize return on energy expenditure. Our data suggest that increased dopamine decreases thriftiness, facilitating energy expenditure, and permitting greater exploration. Conversely, this implies that decreased dopamine increases thriftiness, favoring the exploitation of prior reward learning, and diminishing exploration. This perspective provides a different window onto the role dopamine may play in behavioral flexibility and its failure, compulsive behavior.

VLSI Implementation of a 2.8 Gevent/s Packet-Based AER Interface with Routing and Event Sorting Functionality

October 2011


481 Reads

State-of-the-art large-scale neuromorphic systems require sophisticated spike event communication between units of the neural network. We present a high-speed communication infrastructure for a waferscale neuromorphic system, based on application-specific neuromorphic communication ICs in an field programmable gate arrays (FPGA)-maintained environment. The ICs implement configurable axonal delays, as required for certain types of dynamic processing or for emulating spike-based learning among distant cortical areas. Measurements are presented which show the efficacy of these delays in influencing behavior of neuromorphic benchmarks. The specialized, dedicated address-event-representation communication in most current systems requires separate, low-bandwidth configuration channels. In contrast, the configuration of the waferscale neuromorphic system is also handled by the digital packet-based pulse channel, which transmits configuration data at the full bandwidth otherwise used for pulse transmission. The overall so-called pulse communication subgroup (ICs and FPGA) delivers a factor 25-50 more event transmission rate than other current neuromorphic communication infrastructures.

The Imaging and Cognition Genetics Conference 2011, ICG 2011: A Meeting of Minds

May 2012


52 Reads

In June 2011, 70 researchers from the disciplines of cognitive science, genetics, psychology, psychiatry, neurobiology, and computer science gathered in Os, Norway, for the first Imaging and Cognition Genetics meeting. The aim of the conference was to discuss progress, enhance collaboration, and maximize the sharing of resources within this new field. In this Perspective, we summarize the major themes that emerged from ICG 2011. The first is the importance of defining cognitive and imaging phenotypes and endophenotypes suitable for genetic analysis. These can come from differential psychology, cognitive science, structural MRI, tractography, and functional imaging. The second theme is the emergence of new methods for the analysis of complex traits. These include advanced computational and statistical techniques for analyzing complex datasets, and new ways of interpreting data from genome-wide association studies, such as jointly evaluating the contribution of SNPs in specific genes and pathways rather than considering single SNPs in isolation. The final theme is the importance of establishing functional correlates of newly identified genetic variants.

Figure 1: Experimental setting for microarray-based transcriptome-wide mRNA profiling and 3D-HPLC fingerprint of ADAPT-232.
Figure 2: Venn diagrams of deregulated genes induced by the treatment of neuroglial cells with Rhodiola rosea root, Schisandra chinensis berries, and Eleutherococcus senticosus root extracts alone and their fixed combination, ADAPT-232. (A) The number of unique genes deregulated by each extract alone and the number of deregulated genes that overlapped multiple extracts. (B) Pool of all genes whose expression was affected by any of the three extracts alone in comparison to ADAPT-232.
Table 2 | Primer nucleotide sequences and used primer concentrations.
Figure 3: Hypothetic molecular mechanisms by which adaptogens activate adaptive stress response pathways. Neurons normally receive signals from multiple extracellular stressors that activate adaptive cellular signaling pathways, e.g., many neurotransmitters activate GTP-binding protein coupled receptors (GPCR). The receptors in turn activate kinase cascades including those that activate protein kinase C (PKC), activate protein kinase A (PKA), and phosphatidylinositol-3-kinase (PI3K). Effect of adaptogens on G-protein-coupled receptors pathways: up-regulated genes are represented in red, down-regulated in blue color. The Gs alpha subunit (or Gs protein) activates the cAMP-dependent pathway by activating adenylate cyclase. Gi alpha subunit (or Gi/G0 or Gi protein) inhibits the production of cAMP from ATP. DAG, diacylglycerol; IP3, inositol triphosphate; PLC, phospholipase C.
Table 7 | Top down-regulated genes in schisandrin B-treated T98G cells as investigated by Ingenuity Pathway analysis.
Synergy and Antagonism of Active Constituents of ADAPT-232 on Transcriptional Level of Metabolic Regulation of Isolated Neuroglial Cells

February 2013


417 Reads

Gene expression profiling was performed on the human neuroglial cell line T98G after treatment with adaptogen ADAPT-232 and its constituents – extracts of Eleutherococcus senticosus root, Schisandra chinensis berry, and Rhodiola rosea root as well as several constituents individually, namely, eleutheroside E, schizandrin B, salidroside, triandrin, and tyrosol. A common feature for all tested adaptogens was their effect on G-protein-coupled receptor (GPCR) signaling pathways, i.e. cAMP, phospholipase C and phosphatidylinositol signal transduction pathways. Adaptogens may reduce the cAMP level in brain cells by downregulation of adenylate cyclase gene ADC2Y and upregulation of phosphodiestherase gene PDE4D that is essential for energy homeostasis as well as for switching from catabolic to anabolic states and vice versa. All tested adaptogens up-regulated the PLCB1 gene, which encodes phosphoinositide-specific phospholipase C (PLC) and phosphatidylinositol 3-kinases (PI3Ks), key players for the regulation of NF-B-mediated defense responses. Other common targets of adaptogens included genes encoding ERα estrogen receptor(2.9-22.6 fold down-regulation), cholesterol ester transfer protein (5.1-10.6 fold down-regulation), heat shock protein Hsp70 (3.0-45.0 fold up-regulation), serpin peptidase inhibitor (neuroserpin), and 5-HT3 receptor of serotonin (2.2-6.6 fold down-regulation). These findings can be reconciled with the observed beneficial effects of adaptogens in behavioral, mental and aging-associated disorders. Combining two or more active substances in one mixture significantly changes deregulated genes profiles: synergetic interactions result in activation of genes that none of the individual substances affected, while antagonistic interactions result in suppression some genes activated by individual substances. Merging of deregulated genes array profiles and intracellular networks is specific to the new substance with unique pharmacological characteristics.

In Silico Enhanced Restriction Enzyme Based Methylation Analysis of the Human Glioblastoma Genome Using Agilent 244K CpG Island Microarrays

December 2009


231 Reads

Genome wide methylation profiling of gliomas is likely to provide important clues to improving treatment outcomes. Restriction enzyme based approaches have been widely utilized for methylation profiling of cancer genomes and will continue to have importance in combination with higher density microarrays. With the availability of the human genome sequence and microarray probe sequences, these approaches can be readily characterized and optimized via in silico modeling. We adapted the previously described HpaII/MspI based Methylation Sensitive Restriction Enzyme (MSRE) assay for use with two-color Agilent 244K CpG island microarrays. In this assay, fragmented genomic DNA is digested in separate reactions with isoschizomeric HpaII (methylation-sensitive) and MspI (methylation-insensitive) restriction enzymes. Using in silico hybridization, we found that genomic fragmentation with BfaI was superior to MseI, providing a maximum effective coverage of 22,362 CpG islands in the human genome. In addition, we confirmed the presence of an internal control group of fragments lacking HpaII/MspI sites which enable separation of methylated and unmethylated fragments. We used this method on genomic DNA isolated from normal brain, U87MG cells, and a glioblastoma patient tumor sample and confirmed selected differentially methylated CpG islands using bisulfite sequencing. Along with additional validation points, we performed a receiver operating characteristics (ROC) analysis to determine the optimal threshold (p </= 0.001). Based on this threshold, we identified approximately 2,400 CpG islands common to all three samples and 145 CpG islands unique to glioblastoma. These data provide general guidance to individuals seeking to maximize effective coverage using restriction enzyme based methylation profiling approaches.

The rho kinase inhibitor Y-27632 improves motor performance in male SOD1(G93A) mice

October 2014


223 Reads

Disease progression in amyotrophic lateral sclerosis (ALS) is characterized by degeneration of motoneurons and their axons which results in a progressive muscle weakness and ultimately death from respiratory failure. The only approved drug, riluzole, lacks clinical efficacy so that more potent treatment options are needed. We have identified rho kinase (ROCK) as a target, which can be manipulated to beneficially influence disease progression in models of ALS. Here, we examined the therapeutic potential of the ROCK inhibitor Y-27632 in both an in vitro and in an in vivo paradigm of motoneuron disease. Application of Y-27632 to primary motoneurons in vitro increased survival and promoted neurite outgrowth. In vivo, SOD1(G93A) mice were orally treated with 2 or 30 mg/kg body weight of Y-27632. The 2 mg/kg group did not benefit from Y-27632 treatment, whereas treatment with 30 mg/kg resulted in improved motor function in male mice. Female mice showed only limited improvement and overall survival was not modified in both 2 and 30 mg/kg Y-27632 groups. In conclusion, we provide evidence that inhibition of ROCK by Y-27632 is neuroprotective in vitro but has limited beneficial effects in vivo being restricted to male mice. Therefore, the evaluation of ROCK inhibitors in preclinical models of ALS should always take gender differences into account.

FIGURE 2 | The illustration on the extraction of a single-trial EEG segment from the training data for the multi-class FBCSP training phase in Dataset 2a, and the generation of the
Table 4 | Classification results from using CSP and the FBCSP
Architecture of the filter bank common spatial pattern (FBCSP) algorithm for the training and evaluation phases.
The illustration on the extraction of a single-trial EEG segment from the training data for the multi-class FBCSP training phase in Dataset 2a, and the generation of the classification outputs using the multi-class extension to FBCSP on the entire time segment of a single-trial for the evaluation phase.
The illustration on the extraction of a single-trial EEG segment from the training data for the FBCSP training phase in Dataset 2b, and the generation of the classification outputs using FBCSP on the entire time segment of a single-trial for the evaluation phase.
Filter Bank Common Spatial Pattern Algorithm on BCI Competition IV Datasets 2a and 2b

March 2012


1,985 Reads

The Common Spatial Pattern (CSP) algorithm is an effective and popular method for classifying 2-class motor imagery electroencephalogram (EEG) data, but its effectiveness depends on the subject-specific frequency band. This paper presents the Filter Bank Common Spatial Pattern (FBCSP) algorithm to optimize the subject-specific frequency band for CSP on Datasets 2a and 2b of the Brain-Computer Interface (BCI) Competition IV. Dataset 2a comprised 4 classes of 22 channels EEG data from 9 subjects, and Dataset 2b comprised 2 classes of 3 bipolar channels EEG data from 9 subjects. Multi-class extensions to FBCSP are also presented to handle the 4-class EEG data in Dataset 2a, namely, Divide-and-Conquer (DC), Pair-Wise (PW), and One-Versus-Rest (OVR) approaches. Two feature selection algorithms are also presented to select discriminative CSP features on Dataset 2b, namely, the Mutual Information-based Best Individual Feature (MIBIF) algorithm, and the Mutual Information-based Rough Set Reduction (MIRSR) algorithm. The single-trial classification accuracies were presented using 10 × 10-fold cross-validations on the training data and session-to-session transfer on the evaluation data from both datasets. Disclosure of the test data labels after the BCI Competition IV showed that the FBCSP algorithm performed relatively the best among the other submitted algorithms and yielded a mean kappa value of 0.569 and 0.600 across all subjects in Datasets 2a and 2b respectively.

Impact of RNA Editing on Functions of the Serotonin 2C Receptor in vivo

March 2010


344 Reads

Transcripts encoding 5-HT(2C) receptors are modified posttranscriptionally by RNA editing, generating up to 24 protein isoforms. In recombinant cells, the fully edited isoform, 5-HT(2C-VGV), exhibits blunted G-protein coupling and reduced constitutive activity. The present studies examine the signal transduction properties of 5-HT(2C-VGV) receptors in brain to determine the in vivo consequences of altered editing. Using mice solely expressing the 5-HT(2C-VGV) receptor (VGV/Y), we demonstrate reduced G-protein coupling efficiency and high-affinity agonist binding of brain 5-HT(2C-VGV) receptors. However, enhanced behavioral sensitivity to a 5-HT(2C) receptor agonist was also seen in mice expressing 5-HT(2C-VGV) receptors, an unexpected finding given the blunted G-protein coupling. In addition, mice expressing 5-HT(2C-VGV) receptors had greater sensitivity to a 5-HT(2C) inverse agonist/antagonist enhancement of dopamine turnover relative to wild-type mice. These behavioral and biochemical results are most likely explained by increases in 5-HT(2C) receptor binding sites in the brains of mice solely expressing 5-HT(2C-VGV) receptors. We conclude that 5-HT(2C-VGV) receptor signaling in brain is blunted, but this deficiency is masked by a marked increase in 5-HT(2C) receptor binding site density in mice solely expressing the VGV isoform. These findings suggest that RNA editing may regulate the density of 5-HT(2C) receptor binding sites in brain. We further caution that the pattern of 5-HT(2C) receptor RNA isoforms may not reflect the pattern of protein isoforms, and hence the inferred overall function of the receptor.

On the use of Orientation Filters for 3D Reconstruction in Event-Driven Stereo Vision

March 2014


390 Reads

The recently developed Dynamic Vision Sensors (DVS) sense visual information asynchronously and code it into trains of events with sub-micro second temporal resolution. This high temporal precision makes the output of these sensors especially suited for dynamic 3D visual reconstruction, by matching corresponding events generated by two different sensors in a stereo setup. This paper explores the use of Gabor filters to extract information about the orientation of the object edges that produce the events, therefore increasing the number of constraints applied to the matching algorithm. This strategy provides more reliably matched pairs of events, improving the final 3D reconstruction.

Figure 1: Effect of drug treatments on morphology and expression of GFAP and AHNAK in astrocytes cultured on different substrates. Astrocytes were treated for 72 h with vehicle (Control), dbcAMP (1 mM), Fasudil (100 μM) or Y27632 (30 μM) on glass coverslips, random or aligned bioscaffolds and immunostained to reveal GFAP (green) or AHNAK (red). Paired images represent the same field. Scale bar = 50 μm.
Figure 2: Effect of drug treatments on expression of G-actin and F-actin in astrocytes cultured on different substrates. Astrocytes were treated for 72 h with vehicle (Control), dbcAMP (1 mM), Fasudil (100 μM) or Y27632 (30 μM) on glass coverslips, random or aligned bioscaffolds and labeled to reveal G-actin (green) or F-actin (red). Paired images represent the same field. Scale bar = 50 μm.
Figure 3: Image analysis of difference in integrated density for F-/G- actin ratio. Astrocytes were treated for 72 h with vehicle (Control), dbcAMP (1 mM), Fasudil (100 μM) or Y27632 (30 μM) on glass coverslips, random bioscaffolds or aligned bioscaffolds. *Significantly different from control on same substrate, p < 0.05. Comparisons were made using Two-Way repeated measures ANOVA with Bonferroni's post-hoc test. Data represent mean ± S.E.M. n = 6 (duplicates from 3 individual experiments).
Figure 4: Effect of drug treatments on cell viability and cell damage. Astrocytes were treated for 72 h with vehicle (Control), dbcAMP (1 mM), Fasudil (100 μM) or Y27632 (30 μM) on glass coverslips, random or aligned bioscaffolds. Cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (A), while cell damage was assessed using the lactate dehydrogenase assay (B). *Significantly different from control on same substrate, p < 0.05. Comparisons were made using Two-Way repeated-measures ANOVA with Bonferroni's post-hoc test. Data represent mean ± S.E.M. from 3 independent experiments with the average value from each experiment being n = 1.
Transcriptomic analysis and 3D bioengineering of astrocytes indicate ROCK inhibition produces cytotrophic astrogliosis

February 2015


163 Reads

Astrocytes provide trophic, structural and metabolic support to neurons, and are considered genuine targets in regenerative neurobiology, as their phenotype arbitrates brain integrity during injury. Inhibitors of Rho kinase (ROCK) cause stellation of cultured 2D astrocytes, increased L-glutamate transport, augmented G-actin, and elevated expression of BDNF and anti-oxidant genes. Here we further explored the signposts of a cytotrophic, "healthy" phenotype by data-mining of our astrocytic transcriptome in the presence of Fasudil. Gene expression profiles of motor and autophagic cellular cascades and inflammatory/angiogenic responses were all inhibited, favoring adoption of an anti-migratory phenotype. Like ROCK inhibition, tissue engineered bioscaffolds can influence the extracellular matrix. We built upon our evidence that astrocytes maintained on 3D poly-ε-caprolactone (PCL) electrospun scaffolds adopt a cytotrophic phenotype similar to that produced by Fasudil. Using these procedures, employing mature 3D cultured astrocytes, Fasudil (100 μM) or Y27632 (30 μM) added for the last 72 h of culture altered arborization, which featured numerous additional minor processes as shown by GFAP and AHNAK immunolabelling. Both ROCK inhibitors decreased F-actin, but increased G-actin labeling, indicative of disassembly of actin stress fibers. ROCK inhibitors provide additional beneficial effects for bioengineered 3D astrocytes, including enlargement of the overall arbor. Potentially, the combined strategy of bio-compatible scaffolds with ROCK inhibition offers unique advantages for the management of glial scarring. Overall these data emphasize that manipulation of the astrocyte phenotype to achieve a "healthy biology" offers new hope for the management of inflammation in neuropathologies.

Robotic Goalie with 3ms Reaction Time at 4% CPU Load Using Event-Based Dynamic Vision Sensor

November 2013


2,198 Reads

Conventional vision-based robotic systems that must operate quickly require high video frame rates and consequently high computational costs. Visual response latencies are lower-bound by the frame period, e.g., 20 ms for 50 Hz frame rate. This paper shows how an asynchronous neuromorphic dynamic vision sensor (DVS) silicon retina is used to build a fast self-calibrating robotic goalie, which offers high update rates and low latency at low CPU load. Independent and asynchronous per pixel illumination change events from the DVS signify moving objects and are used in software to track multiple balls. Motor actions to block the most "threatening" ball are based on measured ball positions and velocities. The goalie also sees its single-axis goalie arm and calibrates the motor output map during idle periods so that it can plan open-loop arm movements to desired visual locations. Blocking capability is about 80% for balls shot from 1 m from the goal even with the fastest-shots, and approaches 100% accuracy when the ball does not beat the limits of the servo motor to move the arm to the necessary position in time. Running with standard USB buses under a standard preemptive multitasking operating system (Windows), the goalie robot achieves median update rates of 550 Hz, with latencies of 2.2 ± 2 ms from ball movement to motor command at a peak CPU load of less than 4%. Practical observations and measurements of USB device latency are provided.

Quantitative multi-parameter mapping of R1, PD*, MT, and R2* at 3T: A multi-center validation

June 2013


600 Reads

Multi-center studies using magnetic resonance imaging facilitate studying small effect sizes, global population variance and rare diseases. The reliability and sensitivity of these multi-center studies crucially depend on the comparability of the data generated at different sites and time points. The level of inter-site comparability is still controversial for conventional anatomical T1-weighted MRI data. Quantitative multi-parameter mapping (MPM) was designed to provide MR parameter measures that are comparable across sites and time points, i.e., 1 mm high-resolution maps of the longitudinal relaxation rate (R1 = 1/T1), effective proton density (PD(*)), magnetization transfer saturation (MT) and effective transverse relaxation rate (R2(*) = 1/T2(*)). MPM was validated at 3T for use in multi-center studies by scanning five volunteers at three different sites. We determined the inter-site bias, inter-site and intra-site coefficient of variation (CoV) for typical morphometric measures [i.e., gray matter (GM) probability maps used in voxel-based morphometry] and the four quantitative parameters. The inter-site bias and CoV were smaller than 3.1 and 8%, respectively, except for the inter-site CoV of R2(*) (<20%). The GM probability maps based on the MT parameter maps had a 14% higher inter-site reproducibility than maps based on conventional T1-weighted images. The low inter-site bias and variance in the parameters and derived GM probability maps confirm the high comparability of the quantitative maps across sites and time points. The reliability, short acquisition time, high resolution and the detailed insights into the brain microstructure provided by MPM makes it an efficient tool for multi-center imaging studies.

Effects and Mechanisms of 3α,5α,-THP on Emotion, Motivation, and Reward Functions Involving Pregnane Xenobiotic Receptor

January 2011


153 Reads

Progestogens [progesterone (P(4)) and its products] play fundamental roles in the development and/or function of the central nervous system during pregnancy. We, and others, have investigated the role of pregnane neurosteroids for a plethora of functional effects beyond their pro-gestational processes. Emerging findings regarding the effects, mechanisms, and sources of neurosteroids have challenged traditional dogma about steroid action. How the P(4) metabolite and neurosteroid, 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP), influences cellular functions and behavioral processes involved in emotion/affect, motivation, and reward, is the focus of the present review. To further understand these processes, we have utilized an animal model assessing the effects, mechanisms, and sources of 3α,5α-THP. In the ventral tegmental area (VTA), 3α,5α-THP has actions to facilitate affective, and motivated, social behaviors through non-traditional targets, such as GABA, glutamate, and dopamine receptors. 3α,5α-THP levels in the midbrain VTA both facilitate, and/or are enhanced by, affective and social behavior. The pregnane xenobiotic receptor (PXR) mediates the production of, and/or metabolism to, various neurobiological factors. PXR is localized to the midbrain VTA of rats. The role of PXR to influence 3α,5α-THP production from central biosynthesis, and/or metabolism of peripheral P(4), in the VTA, as well as its role to facilitate, or be increased by, affective/social behaviors is under investigation. Investigating novel behavioral functions of 3α,5α-THP extends our knowledge of the neurobiology of progestogens, relevant for affective/social behaviors, and their connections to systems that regulate affect and motivated processes, such as those important for stress regulation and neuropsychiatric disorders (anxiety, depression, schizophrenia, drug dependence). Thus, further understanding of 3α,5α-THP's role and mechanisms to enhance affective and motivated processes is essential.

Ro 15-4513 Antagonizes Alcohol-Induced Sedation in Mice Through αβγ2-type GABAA Receptors

January 2011


128 Reads

Ethyl alcohol (ethanol) has many molecular targets in the nervous system, its potency at these sites being low compared to those of sedative drugs. This has made it difficult to discover ethanol's binding site(s). There are two putative binding sites at γ-aminobutyric acid (GABA) type A receptor subtypes for the proposed ethanol antagonist Ro 15-4513, the established γ2 subunit-dependent benzodiazepine site and the recently reported δ subunit-dependent Ro 15-4513/ethanol binding site. Here, we aimed at clarifying the in vivo role of Ro 15-4513 at these two sites. We found that the antagonism of ethanol actions by Ro 15-4513 in wildtype mice was dependent on the test: an open field test showed that light sedation induced by 1.5-1.8 g/kg ethanol was sensitive to Ro 15-4513, whereas several tests for ethanol-induced anxiolytic effects showed that the ethanol-induced effects were insensitive to Ro 15-4513. Antagonism of ethanol-induced sedation by Ro 15-4513 was unaffected in GABA(A) receptor δ subunit knockout mice. By contrast, when testing the GABA(A) receptor γ2 subunit F77I knock-in mouse line (γ2I77 mice) with its strongly reduced affinity of the benzodiazepine sites for Ro 15-4513, we found that the ethanol-induced sedation was no longer antagonized by Ro 15-4513. Indeed, γ2I77 mice had only a small proportion of high-affinity binding of [(3)H]Ro 15-4513 left as compared to wildtype mice, especially in the caudate-putamen and septal areas, but these residual sites are apparently not involved in ethanol antagonism. In conclusion, we found that Ro 15-4513 abolished the sedative effect of ethanol by an action on γ2 subunit-dependent benzodiazepine sites.

Pharmacological Preconditioning with GYKI 52466: A Prophylactic Approach to Neuroprotection

August 2010


198 Reads

Some toxins and drugs can trigger lasting neuroprotective mechanisms that enable neurons to resist a subsequent severe insult. This "pharmacological preconditioning" has far-reaching implications for conditions in which blood flow to the brain is interrupted. We have previously shown that in vitro preconditioning with the AMPA receptor antagonist GYKI 52466 induces tolerance to kainic acid (KA) toxicity in hippocampus. This effect persists well after washout of the drug and may be mediated via inverse agonism of G-protein coupled receptors (GPCRs). Given the amplifying nature of metabotropic modulation, we hypothesized that GYKI 52466 may be effective in reducing seizure severity at doses well below those normally associated with adverse side effects. Here we report that pharmacological preconditioning with low-dose GYKI imparts a significant protection against KA-induced seizures in vivo. GYKI (3 mg/kg, s.c.), 90-180 min prior to high-dose KA, markedly reduced seizure scores, virtually abolished all level 3 and level 4 seizures, and completely suppressed KA-induced hippocampal c-FOS expression. In addition, preconditioned animals exhibited significant reductions in high frequency/high amplitude spiking and ECoG power in the delta, theta, alpha, and beta bands during KA. Adverse behaviors often associated with higher doses of GYKI were not evident during preconditioning. The fact that GYKI is effective at doses well-below, and at pre-administration intervals well-beyond previous studies, suggests that a classical blockade of ionotropic AMPA receptors does not underlie anticonvulsant effects. Low-dose GYKI preconditioning may represent a novel, prophylactic strategy for neuroprotection in a field almost completely devoid of effective pharmaceuticals.

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