Neuroimaging in specific phobia disorder: a systematic review of the literature

OBJECTIVE: Specific phobia (SP) is characterized by irrational fear associated with avoidance of specific stimuli. In recent years, neuroimaging techniques have been used in an attempt to better understand the neurobiology of anxiety disorders. The objective of this study was to perform a systematic review of articles that used neuroimaging techniques to study SP. METHOD:A literature search was conducted through electronic databases, using the keywords: imaging, neuroimaging, PET, spectroscopy, functional magnetic resonance, structural magnetic resonance, SPECT, MRI, DTI, and tractography, combined with simple phobia and specific phobia. One-hundred fifteen articles were found, of which 38 were selected for the present review. From these, 24 used fMRI, 11 used PET, 1 used SPECT, 2 used structural MRI, and none used spectroscopy. RESULT: The search showed that studies in this area were published recently and that the neuroanatomic substrate of SP has not yet been consolidated. CONCLUSION: In spite of methodological differences among studies, results converge to a greater activation in the insula, anterior cingulate cortex, amygdala, and prefrontal and orbitofrontal cortex of patients exposed to phobia-related situations compared to controls. These findings support the hypotheses of the hyperactivation of a neuroanatomic structural network involved in SP.

Psychiatric comorbidities in temporal lobe epilepsy: possible relationships between psychotic disorders and involvement of limbic circuits

OBJECTIVE: Mounting evidence suggests that the limbic system is pathologically involved in cases of psychiatric comorbidities in temporal lobe epilepsy (TLE) patients. Our objective was to develop a conceptual framework describing how neuropathological and connectivity changes might contribute to the development of psychosis and to the potential neurobiological mechanisms that cause schizophrenia-like psychosis in TLE patients. METHODS: In this review, clinical and neuropathological findings, especially brain circuitry of the limbic system, were examined together to enhance our understanding of the association between TLE and psychosis. Finally, the importance of animal models in epilepsy and psychiatric disorders was discussed. CONCLUSIONS: TLE and psychiatric symptoms coexist more frequently than chance would predict. Damage and deregulation among critical anatomical regions, such as the hippocampus, amygdala, thalamus, and the temporal, frontal and cingulate cortices, might predispose TLE brains to psychosis. Studies of the effects of kindling and injection of neuroactive substances on behavior and electrophysiological patterns may offer a model of how limbic seizures in humans increase the vulnerability of TLE patients to psychiatric symptoms.

Chronic unpredictable mild stress alters an anxiety-related defensive response, Fos immunoreactivity and hippocampal adult neurogenesis

Previous results show that elevated T-maze (ETM) avoidance responses are facilitated by acute restraint. Escape, on the other hand, was unaltered. To examine if the magnitude of the stressor is an important factor influencing these results, we investigated the effects of unpredictable chronic mild stress (UCMS) on ETM avoidance and escape measurements. Analysis of Fos protein immunoreactivity (Fos-ir) was used to map areas activated by stress exposure in response to ETM avoidance and escape performance. Additionally, the effects of the UCMS protocol on the number of cells expressing the marker of migrating neuroblasts doublecortin (DCX) in the hippocampus were investigated. Corticosterone serum levels were also measured. Results showed that UCMS facilitates ETM avoidance, not altering escape. In unstressed animals, avoidance performance increases Fos-ir in the cingulate cortex, hippocampus (dentate gyrus) and basomedial amygdala, and escape increases Fos-ir in the dorsolateral periaqueductal gray and locus ceruleus. In stressed animals submitted to ETM avoidance, increases in Fos-ir were observed in the cingulate cortex, ventrolateral septum, hippocampus, hypothalamus, amygdala, dorsal and median raphe nuclei. In stressed animals submitted to ETM escape, increases in Fos-ir were observed in the cingulate cortex, periaqueductal gray and locus ceruleus. Also, UCMS exposure decreased the number of DCX-positive cells in the dorsal and ventral hippocampus and increased corticosterone serum levels. These data suggest that the anxiogenic effects of UCMS are related to the activation of specific neurobiological circuits that modulate anxiety and confirm that this stress protocol activates the hypothalamus-pituitary-adrenal axis and decreases hippocampal adult neurogenesis.

ANP impairs the dose-dependent stimulatory effect of ANG II or AVP on H+-ATPase subcellular vesicle trafficking

The effect of angiotensin II (ANG II) or arginine vasopressin (AVP) alone or plus atrial natriuretic peptide (ANP) on H+-ATPase subcellular vesicle trafficking was investigated in MDCK cells following intracellular pH (pHi) acidification by exposure to20 mMNH4Cl for 2 min in a Na+-free solution containing Schering 28080, conditions under which H+-AT-Pase is the only cell mechanism for pHi recovery. Using the acridine orange fluorescent probe (5mM) and confocal microscopy, the vesicle movement was quantified by determining, for each experimental group, the mean slope of the line indicating the changes in apical/basolateral fluorescence density ratio over time during the first 5.30 min of the pHi recovery period. Under the control conditions, the mean slope was 0.079 ± 0.0033 min-1 (14) and it increased significantly with ANG II [10-12 and 10-7 M, respectively to 0.322 ± 0.038 min-1 (13) and 0.578 ± 0.061 min-1 (12)] or AVP [10-12 and 10-6 M, respectively to 0.301 ± 0.018 min-1 (12) and 0.687 ± 0.049 min-1 (11)]. However, in presence of ANP (10-6 M, decreases cytosolic free calcium), dimethyl-BAPTA/AM (5 × 10-5 M, chelates intracellular calcium) or colchicine (10-5 M, 2-h preincubation; inhibits microtubule-dependent vesicular trafficking) alone or plus ANG II or AVP the mean slopes were similar to the control values, indicating that such agents blocked the stimulatory effect of ANG II or AVP on vesicle trafficking. The results suggest that the pathway responsible for the increase in cytosolic free calcium and the microtu-bule-dependent vesicular trafficking are involved in this hormonal stimulating effect. Whether cytosolic free calcium reduction represents an important direct mechanism for ANP impairs the dose-dependent stimulatory effect of ANG II or AVP on H+-ATPase subcellular vesicle trafficking, or is a side effect of other signaling pathways which will require additional studies.

Nuovo modello animale per lo studio della working memory: validazione farmacologica e applicazioni

The present study was performed to validate a spatial working memory task using pharmacological manipulations. The water escape T-maze, which combines the advantages of the Morris water maze and the T-maze while minimizes the disadvantages, was used. Scopolamine, a drug that affects cognitive function in spatial working memory tasks, significantly decreased the rat performance in the present delayed alternation task. Since glutamate neurotransmission plays an important role in the maintaining of working memory, we evaluated the effect of ionotropic and metabotropic glutamatergic receptors antagonists, administered alone or in combination, on rat behaviour. As the acquisition and performance of memory tasks has been linked to the expression of the immediately early gene cFos, a marker of neuronal activation, we also investigated the neurochemical correlates of the water escape T-maze after pharmacological treatment with glutamatergic antagonists, in various brain areas. Moreover, we focused our attention on the involvement of perirhinal cortex glutamatergic neurotransmission in the acquisition and/or consolidation of this particular task. The perirhinal cortex has strong and reciprocal connections with both specific cortical sensory areas and some memory-related structures, including the hippocampal formation and amygdala. For its peculiar position, perirhinal cortex has been recently regarded as a key region in working memory processes, in particular in providing temporary maintenance of information. The effect of perirhinal cortex lesions with ibotenic acid on the acquisition and consolidation of the water escape T-maze task was evaluated. In conclusion, our data suggest that the water escape T-maze could be considered a valid, simple and quite fast method to assess spatial working memory, sensible to pharmacological manipulations. Following execution of the task, we observed cFos expression in several brain regions. Furthermore, in accordance to literature, our results suggest that glutamatergic neurotransmission plays an important role in the acquisition and consolidation of working memory processes.

Neural basis of visual deficits recovery: visual residual functions and multisensory integration.

The ability of integrating into a unified percept sensory inputs deriving from different sensory modalities, but related to the same external event, is called multisensory integration and might represent an efficient mechanism of sensory compensation when a sensory modality is damaged by a cortical lesion. This hypothesis has been discussed in the present dissertation. Experiment 1 explored the role of superior colliculus (SC) in multisensory integration, testing patients with collicular lesions, patients with subcortical lesions not involving the SC and healthy control subjects in a multisensory task. The results revealed that patients with collicular lesions, paralleling the evidence of animal studies, demonstrated a loss of multisensory enhancement, in contrast with control subjects, providing the first lesional evidence in humans of the essential role of SC in mediating audio-visual integration. Experiment 2 investigated the role of cortex in mediating multisensory integrative effects, inducing virtual lesions by inhibitory theta-burst stimulation on temporo-parietal cortex, occipital cortex and posterior parietal cortex, demonstrating that only temporo-parietal cortex was causally involved in modulating the integration of audio-visual stimuli at the same spatial location. Given the involvement of the retino-colliculo-extrastriate pathway in mediating audio-visual integration, the functional sparing of this circuit in hemianopic patients is extremely relevant in the perspective of a multisensory-based approach to the recovery of unisensory defects. Experiment 3 demonstrated the spared functional activity of this circuit in a group of hemianopic patients, revealing the presence of implicit recognition of the fearful content of unseen visual stimuli (i.e. affective blindsight), an ability mediated by the retino-colliculo-extrastriate pathway and its connections with amygdala. Finally, Experiment 4 provided evidence that a systematic audio-visual stimulation is effective in inducing long-lasting clinical improvements in patients with visual field defect and revealed that the activity of the spared retino-colliculo-extrastriate pathway is responsible of the observed clinical amelioration, as suggested by the greater improvement observed in patients with cortical lesions limited to the occipital cortex, compared to patients with lesions extending to other cortical areas, found in tasks high demanding in terms of spatial orienting. Overall, the present results indicated that multisensory integration is mediated by the retino-colliculo-extrastriate pathway and that a systematic audio-visual stimulation, activating this spared neural circuit, is able to affect orientation towards the blind field in hemianopic patients and, therefore, might constitute an effective and innovative approach for the rehabilitation of unisensory visual impairments.

Applicazione della neurodiagnostica avanzata allo studio dei disturbi psicologici nelle malattie infiammatorie croniche intestinali

Background and aim Ulcerative Colitis (UC) and Crohn’s Disease (CD), collectively labelled as inflammatory bowel disease (IBD), are idiopathic, chronic inflammatory disorder of the bowel with a remitting and relapsing course. IBD are associated to poor emotional functioning and psychological distress. We have investigated the brain involvement in patients with IBD using functional magnetic resonance imaging (fMRI). Materials and methods We developed an emotional visual task to investigate the emotional functioning in 10 UC patients and 10 healthy controls (HC). Furthermore, we have compared the brain stress response between a group of 20 CD patients and a group of 18 HC. Finally, we evaluated potential morphological differences between 18 CD patients and 18 HC in a voxel based morphometry (VBM) study. Results We found brain functional changes in UC patients characterized by decreased activity in the amygdala in response to positive emotional stimuli. Moreover, in CD patients, the brain stress response and habituation to stressful stimuli were significantly different in the medial temporal lobe (including the amygdala and hippocampus), the insula and cerebellum. Finally, in CD patients there were morphological abnormalities in the anterior mid cingulated cortex (aMCC). Conclusion IBD are associated to functional and morphological brain abnormalities. The previous intestinal inflammatory activity in IBD patients might have contributed to determine the functional and morphological changes we found. On the other hand, the dysfunctions of the brain structures we found may influence the course of the disease. Our findings might have clinical implications. The differences in the emotional processing may play a role in the development of psychological disorders in UC patients. Furthermore, in CD patients, the different habituation to stress might contribute to stress related inflammatory exacerbations. Finally, the structural changes in the aMCC might be involved in the pain symptoms associated to the bowel disorder.

Interaction between APOE4 genotype and environmental risk factors in Alzheimer's disease

Alzheimer's disease (AD) is probably caused by both genetic and environmental risk factors. The major genetic risk factor is the E4 variant of apolipoprotein E gene called apoE4. Several risk factors for developing AD have been identified including lifestyle, such as dietary habits. The mechanisms behind the AD pathogenesis and the onset of cognitive decline in the AD brain are presently unknown. In this study we wanted to characterize the effects of the interaction between environmental risk factors and apoE genotype on neurodegeneration processes, with particular focus on behavioural studies and neurodegenerative processes at molecular level. Towards this aim, we used 6 months-old apoE4 and apoE3 Target Replacement (TR) mice fed on different diets (high intake of cholesterol and high intake of carbohydrates). These mice were evaluated for learning and memory deficits in spatial reference (Morris Water Maze (MWM)) and contextual learning (Passive Avoidance) tasks, which involve the hippocampus and the amygdala, respectively. From these behavioural studies we found that the initial cognitive impairments manifested as a retention deficit in apoE4 mice fed on high carbohydrate diet. Thus, the genetic risk factor apoE4 genotype associated with a high carbohydrate diet seems to affect cognitive functions in young mice, corroborating the theory that the combination of genetic and environmental risk factors greatly increases the risk of developing AD and leads to an earlier onset of cognitive deficits. The cellular and molecular bases of the cognitive decline in AD are largely unknown. In order to determine the molecular changes for the onset of the early cognitive impairment observed in the behavioural studies, we performed molecular studies, with particular focus on synaptic integrity and Tau phosphorylation. The most relevant finding of our molecular studies showed a significant decrease of Brain-derived Neurotrophic Factor (BDNF) in apoE4 mice fed on high carbohydrate diet. Our results may suggest that BDNF decrease found in apoE4 HS mice could be involved in the earliest impairment in long-term reference memory observed in behavioural studies. The second aim of this thesis was to study possible involvement of leptin in AD. There is growing evidence that leptin has neuroprotective properties in the Central Nervous System (CNS). Recent evidence has shown that leptin and its receptors are widespread in the CNS and may provide neuronal survival signals. However, there are still numerous questions, regarding the molecular mechanism by which leptin acts, that remain unanswered. Thus, given to the importance of the involvement of leptin in AD, we wanted to clarify the function of leptin in the pathogenesis of AD and to investigate if apoE genotype affect leptin levels through studies in vitro, in mice and in human. Our findings suggest that apoE4 TR mice showed an increase of leptin in the brain. Leptin levels are also increased in the cerebral spinal fluid of AD patients and apoE4 carriers with AD have higher levels of leptin than apoE3 carriers. Moreover, leptin seems to be expressed by reactive glial cells in AD brains. In vitro, ApoE4 together with Amyloid beta increases leptin production by microglia and astrocytes. Taken together, all these findings suggest that leptin replacement might not be a good strategy for AD therapy. Our results show that high leptin levels were found in AD brains. These findings suggest that, as high leptin levels do not promote satiety in obese individuals, it might be possible that they do not promote neuroprotection in AD patients. Therefore, we hypothesized that AD brain could suffer from leptin resistance. Further studies will be critical to determine whether or not the central leptin resistance in SNC could affect its potential neuroprotective effects.

Elastizität porenüberspannender Membranen: eine kraftmikroskopische Studie

Membranen spielen eine essentielle Rolle bei vielen wichtigen zellulären Prozessen. Sie ermöglichen die Erzeugung von chemischen Gradienten zwischen dem Zellinneren und der Umgebung. Die Zellmembran übernimmt wesentliche Aufgaben bei der intra- und extrazellulären Signalweiterleitung und der Adhäsion an Oberflächen. Durch Prozesse wie Endozytose und Exozytose werden Stoffe in oder aus der Zelle transportiert, eingehüllt in Vesikel, welche aus der Zellmembran geformt werden. Zusätzlich bietet sie auch Schutz für das Zellinnere. Der Hauptbestandteil einer Zellmembran ist die Lipiddoppelschicht, eine zweidimensionale fluide Matrix mit einer heterogenen Zusammensetzung aus unterschiedlichen Lipiden. In dieser Matrix befinden sich weitere Bausteine, wie z.B. Proteine. An der Innenseite der Zelle ist die Membran über Ankerproteine an das Zytoskelett gekoppelt. Dieses Polymernetzwerk erhöht unter anderem die Stabilität, beeinflusst die Form der Zelle und übernimmt Funktionenrnbei der Zellbewegung. Zellmembranen sind keine homogenen Strukturen, je nach Funktion sind unterschiedliche Lipide und Proteine in mikrsokopischen Domänen angereichert.Um die grundlegenden mechanischen Eigenschaften der Zellmembran zu verstehen wurde im Rahmen dieser Arbeit das Modellsystem der porenüberspannenden Membranen verwendet.Die Entwicklung der porenüberspannenden Membranen ermöglicht die Untersuchung von mechanischen Eigenschaften von Membranen im mikro- bis nanoskopischen Bereich mit rasterkraftmikroskopischen Methoden. Hierbei bestimmen Porosität und Porengröße des Substrates die räumliche Auflösung, mit welcher die mechanischen Parameter untersucht werdenrnkönnen. Porenüberspannende Lipiddoppelschichten und Zellmembranen auf neuartigen porösen Siliziumsubstraten mit Porenradien von 225 nm bis 600 nm und Porositäten bis zu 30% wurden untersucht. Es wird ein Weg zu einer umfassenden theoretischen Modellierung der lokalen Indentationsexperimente und der Bestimmung der dominierenden energetischen Beiträge in der Mechanik von porenüberspannenden Membranen aufgezeigt. Porenüberspannende Membranen zeigen eine linear ansteigende Kraft mit zunehmender Indentationstiefe. Durch Untersuchung verschiedener Oberflächen, Porengrößen und Membranen unterschiedlicher Zusammensetzung war es für freistehende Lipiddoppelschichten möglich, den Einfluss der Oberflächeneigenschaften und Geometrie des Substrates, sowie der Membranphase und des Lösungsmittels auf die mechanischen Eigenschaften zu bestimmen. Es ist möglich, die experimentellen Daten mit einem theoretischen Modell zu beschreiben. Hierbei werden Parameter wie die laterale Spannung und das Biegemodul der Membran bestimmt. In Abhängigkeit der Substrateigenschaften wurden für freitragende Lipiddoppelschichten laterale Spannungen von 150 μN/m bis zu 31 mN/m gefunden für Biegemodulde zwischen 10^(−19) J bis 10^(−18) J. Durch Kraft-Indentations-Experimente an porenüberspannenden Zellmembranen wurde ein Vergleich zwischen dem Modell der freistehenden Lipiddoppelschichten und nativen Membranen herbeigeführt. Die lateralen Spannungen für native freitragende Membranen wurden zu 50 μN/m bestimmt. Weiterhin konnte der Einfluss des Zytoskeletts und der extrazellulä-rnren Matrix auf die mechanischen Eigenschaften bestimmt und innerhalb eines basolateralen Zellmembranfragments kartiert werden, wobei die Periodizität und der Porendurchmesser des Substrates das räumliche Auflösungsvermögen bestimmen. Durch Fixierung der freistehenden Zellmembran wurde das Biegemodul der Membran um bis zu einem Faktor 10 erhöht. Diese Arbeit zeigt wie lokal aufgelöste, mechanische Eigenschaften mittels des Modellsystems der porenüberspannenden Membranen gemessen und quantifiziert werden können. Weiterhin werden die dominierenden energetischen Einflüsse diskutiert, und eine Vergleichbarkeit zurnnatürlichen Membranen hergestellt.rn

Relationship between pain and anxiety in rats

Clinically, it is well known that neuropathic pain often induces comorbid symptoms such as anxiety. In turn, also anxiety has been associated with a heightened experience of pain. Although, the link between pain and anxiety is well recognized in humans, the neurobiological basis of this relationship remains unclear. Therefore, the aim of the current study was to investigate the influence of neuropathic pain on anxiety and vice versa in rats by assessing not only pain-related behaviour but also by discovering possible key substrates which are responsible for the interrelation of pain and anxiety.rnIn rats with a chronic constriction of the sciatic nerve (CCI model) anxiety-like behaviour was observed. Since anxiety behaviour could be completely abolished after the treatment of the pure analgesic drugs gabapentin and morphine, we concluded that anxiety was caused by the strong persistent pain. Furthermore, we found that the neuropeptides oxytocin and vasopressin were upregulated in the amygdala of CCI rats, and the intra-amygdala treatment of an oxytocin antagonist but not the vasopressin antagonist could reduce anxiety-like behaviour in these animals, while no effect on mechanical hypersensitivity was observed. These data indicate that oxytocin is implicated in the underlying neuronal processes of pain-induced anxiety and helps to elucidate the pathophysiological mechanisms of neuropathic pain. rnTo assess the influence of trait anxiety on pain sensation in rats, we determined mechanical hypersensitivity after sciatic nerve lesion (CCI) in animals selectively bred for high anxiety or low anxiety behaviour. The paw withdrawal thresholds were significantly decreased in high anxiety animals in comparison to low anxiety animals 2 and 3 weeks after surgery. In a second model state anxiety was induced by the sub-chronic injection of the anxiogenic drug pentylentetrazol in naive rats. Pain response to mechanical stimuli was increased after pharmacologically-induced anxiety. These results provided evidence for the influence of both trait and state anxiety on pain sensation. rnThe studies contribute to the elucidation of the relationship between pain and anxiety. We investigated that the neuropathic pain model displays sensory as well as emotional factors of peripheral neuropathy. Changes in expression levels of neuropeptides in the central nervous system due to neuropathic pain may contribute to the pathophysiology of neuropathic pain and its related symptoms in animals which might also be relevant for human scenarios. The results of the current study also confirm that anxiety plays an important role in the perception of pain. rnA better understanding of pain behaviour in animals might improve the preclinical profiling of analgesic drugs during development. The study highlights the potential use of the rat model as a new preclinical tool to further investigate the link between pain and anxiety by determining not only the sensory reflexes after painful stimuli but also the more complex pain-related behaviour such as anxiety.rn

Functional and neural mechanisms of intertemporal choice

People are daily faced with intertemporal choice, i.e., choices differing in the timing of their consequences, frequently preferring smaller-sooner rewards over larger-delayed ones, reflecting temporal discounting of the value of future outcomes. This dissertation addresses two main goals. New evidence about the neural bases of intertemporal choice is provided. Following the disruption of either the medial orbitofrontal cortex or the insula, the willingness to wait for larger-delayed outcomes is affected in odd directions, suggesting the causal involvement of these areas in regulating the value computation of rewards available with different timings. These findings were also supported by a reported imaging study. Moreover, this dissertation provides new evidence about how temporal discounting can be modulated at a behavioral level through different manipulations, e.g., allowing individuals to think about the distant time, pairing rewards with aversive events, or changing their perceived spatial position. A relationship between intertemporal choice, moral judgements and aging is also discussed. All these findings link together to support a unitary neural model of temporal discounting according to which signals coming from several cortical (i.e., medial orbitofrontal cortex, insula) and subcortical regions (i.e., amygdala, ventral striatum) are integrated to represent the subjective value of both earlier and later rewards, under the top-down regulation of dorsolateral prefrontal cortex. The present findings also support the idea that the process of outcome evaluation is strictly related to the ability to pre-experience and envision future events through self-projection, the anticipation of visceral feelings associated with receiving rewards, and the psychological distance from rewards. Furthermore, taking into account the emotions and the state of arousal at the time of decision seems necessary to understand impulsivity associated with preferring smaller-sooner goods in place of larger-later goods.

Beeinflusst die Stärke der Stressreaktion in der Post-Akquisitionsphase das Identitätsgedächtnis von Gesichtern?

Stress in der Post-Akquisitionsphase begünstigt die Gedächtniskonsolidierung emotional erregender Informationen. Das Zusammenspiel von noradrenerger Aktivierung und Cortisol auf Ebene der Amygdala ist hierbei von entscheidender Bedeutung. rnIn dieser Studie wird untersucht, ob dieser Effekt durch das Ausmaß der kardiovaskulären bzw. der subjektiv erlebten Stressreaktivität beeinflusst wird. 49 Probanden (Alter: 23.8 Jahre; 32 Frauen) wurden je 52 Gesichter, davon 50% mit ärgerlichem sowie 50 % mit glücklichem Ausdruck präsentiert. Sofort nach Akquisition wurde bei 30 Probanden akuter Stress durch den sozial evaluierten Kaltwassertest (SECPT; Eintauchen der dominanten Hand in eiskaltes Wasser für 3 Minuten unter Beobachtung) induziert, bei 19 Probanden wurde eine Kontrollprozedur ohne Stress durchgeführt. Die 30 Probanden der SECPT-Gruppe wurden post-hoc zum einen anhand der individuellen Blutdruckreaktivität und zum zweiten anhand der Stärke der subjektiv bewerteten Stressreaktivität per Mediansplit in zwei Subgrupen unterteilt (High Responder, Low Responder). rnDer erste Wiedererkennungstest fand 30 Minuten nach der Akquisitionsphase, ein weiterer 20 Stunden später statt. Zu den Testzeitpunkten wurden jeweils 26 der initial präsentierten Gesichter mit neutralem Gesichtsausdruck gezeigt sowie 26 neue neutrale Gesichter. rnDie Kontrollgruppe und die Gruppe der High Responder (basierend auf der kardiovaskulären Reaktivität) zeigten ein besseres Erinnerungsvermögen für die initial positiv präsentierten gesichter, wohingegen die Gruppe der Low Responder ein besseres Gedächtnis für die initial negativ präsentierten Gesichter aufwies. rnStress scheint abhängig von der Stärke der kardiovaskulären Reaktion zu valenzspezifischen Konsolidierungseffekten zu führen. Hierbei könnten viszerale Afferenzen z.B. der arteriellen Baroreflexe eine Rolle spielen. rn

Clostridium difficile toxins facilitate bacterial colonization by modulating the fence and gate function of colonic epithelium

The contribution of Clostridium difficile toxin A and B (TcdA and TcdB) to cellular intoxication has been extensively studied, but their impact on bacterial colonization remains unclear. By setting-up two- and three-dimensional in vitro models of polarized gut epithelium, we investigated how C. difficile infection is affected by host cell polarity and whether TcdA and TcdB contribute to such events. Indeed, we observed that C. difficile adhesion and penetration of the epithelial barrier is substantially enhanced in poorly polarized or EGTA-treated cells, indicating that bacteria bind preferentially to the basolateral cell surface. In this context, we demonstrated that sub-lethal concentrations of C. difficile TcdA are able to alter cell polarity by causing redistribution of plasma membrane components between distinct surface domains. Taken together, the data suggest that toxin-mediated modulation of host cell organization may account for the capacity of this opportunistic pathogen to gain access to basolateral receptors leading to a successful colonization of the colonic mucosa.

Cerebro-corticale und subcorticale Prozessierung vestibulärer Informationen im intakten und lädierten System der Ratte (Micro-PET-Studie)

In dieser Studie wurde anhand des Modells der Ratte das Gleichgewichtssystem auf cerebro-corticaler Ebene untersucht, und das Verhalten des Gehirns nach akuten sowie chronischen Ausfällen mit funktioneller Bildgebung untersucht. rnMit der Positronen-Emissions-Tomographie (PET) kann die Metabolismusrate bestimmter Gehirnareale gemessen werden. Narkotisierte Tiere wurden unter galvanischer vestibulärer Stimulation im PET gemessen und die Ergebnisse wurden mit Kontrollstimulations-Messungen verglichen. Es konnten verschiedene Areale, die eine erhöhte Stoffwechselaktivität aufwiesen, ermittelt werden. Dazu gehören der somatosensorische und der insuläre Cortex, Teile des auditorischen Cortexes, der anteriore cinguläre sowie der entorhinale Cortex. Subcorticale Strukturen wie der Hippocampus, die Amygdala sowie die latero-dorsalen thalamischen Kerne wiesen ebenfalls erhöhten Stoffwechsel unter vestibulärer Stimulation auf. rnBei dieser PET-Studie handelt es sich um die erste funktionell-bildgebende Studie, die Verarbeitung vestibulärer Informationen bei Ratten in vivo darstellt. Die anatomische Verbindung der gefundenen Areale wurde mit anterograden und retrograden neuronalen Tracings unterstützt. rnDarüber hinaus wurde markiertes Gewebe, welches die Verbindung zwischen thalamischen und cerebro-corticalen Kernen der vestibulären Verschaltung aufweist, immunhistochemisch auf dessen Neurotransmission hin untersucht. Das katecholaminergen und dem opioidergen System wurde untersucht. Eine Beteiligung katecholaminerger Transmitter konnte nicht nachgewiesen werden. Neurone im somatosensorischen Cortex, die positiv auf einen Opioid-Rezeptor-Antikörper getestet wurden erhalten anterograd markierte Terminale aus dem thalamischen Kern LDDM, der mittels der PET als vestibulär identifiziert werden konnte. rnBasierend auf den Ergebnissen der ersten bildgebenden Studie wurde in einer zweiten funktionell-bildgebenden Studie die zentral-vestibuläre Verschaltung unterbrochen, indem relevante thalamische Kerngebiete (LDDM, LDVL) elektrolytisch zerstört wurden. Die Stoffwechselaktivität wurde anschließend bei diesen Tieren an verschiedenen Zeitpunkten nach der Läsion im PET unter vestibulärer Stimulation gemessen. Die Stoffwechselaktivität dieser Tiere wurde mit der Stoffwechselaktivität von Kontroll-Tieren verglichen. rnBei dieser Studie wurde zum ersten Mal, mittels funktioneller Bildgebung gezeigt, welche Bereiche des Gehirns nach akuter und chronischer Läsion des vestibulären Systems an Kompensationsmechanismen beteiligt sind. Alle Gehirnareale, die in verschiedenen Zeitfenstern (1, 3, 7 und 20 Tage nach Läsion) erhöhten Metabolismus aufweisen, sind Teil der vestibulären Verschaltung. Es handelt sich dabei um Areale der Okulomotorik und des räumlichen Gedächtnisses: das Postsubiculum, den Colliculus superior, das mediale Corpus geniculatum, den entorhinalen Cortex sowie die Zona incerta.rn

Involvement of the opioid system and BDNF in neuroplastic alterations occurring in neuropathic pain conditions

Chronic pain affects one in five adults, reducing quality of life and increasing risk of developing co-morbidities such as depression. Neuropathic pain results by lesions to the nervous system that alter its structure and function leading to spontaneous pain and amplified responses to noxious and innocuous stimuli. The Opioid System is probably the most important system involved in control of nociceptive transmission. Dynorphin and nociceptin systems have been suggested key mediators of some neuropathic pain aspects. An important role also for BDNF has been recently suggested since its involvement in the peripheral and central sensitization phenomena is known. We studied neuroplastic alterations occurring in chronic pain in mice subjected to the chronic constriction injury (CCI). We investigated gene expression alterations of both BDNF and Opioid System at spinal level at different intervals of time. A transient upregulation of pBDNF and pDYN was observed in spinal cord, while increasing upregulation of ppN/OFQ was found in the DRGs of injured mice. Development of neuropathic behavioral signs has been observed in ICR/CD-1 and BDNF+/+ mice, subjected to CCI. A different development of these signs was observed in BDNF+/-. We also studied gene expression changes of investigated systems in different brain areas fourteen days after surgery. We found pBDNF, pDYN, pKOP, ppN/OFQ and pNOP gene expression alterations in several areas of CCI mice. In the same brain regions we also determined bioactive nociceptin peptide levels, and elevated N/OFQ levels were observed in the amygdala area. Histone modifications studies have been performed in BDNF and DYN gene promoters of CCI animal spinal cord showing selected alterations in pDYN gene promoter. In addition, a preliminary characterization of the innovative NOP-EGFP mice was performed. Overall, our results could be useful to understand which and how neuropeptidergic systems are involved in neuroplastic mechanism occurring in neuropathic pain.