Neural correlates of cue‐induced changes in decision‐making distinguish subjects with gambling disorder from healthy controls

In addiction, there are few human studies on the neural basis of cue-induced changes in value-based decision making (Pavlovian-to-instrumental transfer, PIT). It is especially unclear whether neural alterations related to PIT are due to the physiological effects of substance abuse or rather related to learning processes and/or other etiological factors related to addiction. We have thus investigated whether neural activation patterns during a PIT task help to distinguish subjects with gambling disorder (GD), a nonsubstance-based addiction, from healthy controls (HCs). Thirty GD and 30 HC subjects completed an affective decision-making task in a functional magnetic resonance imaging (fMRI) scanner. Gambling-associated and other emotional cues were shown in the background during the task. Data collection and feature modeling focused on a network of nucleus accumbens (NAcc), amygdala, and orbitofrontal cortex (OFC) (derived from PIT and substance use disorder [SUD] studies). We built and tested a linear classifier based on these multivariate neural PIT signatures. GD subjects showed stronger PIT than HC subjects. Classification based on neural PIT signatures yielded a significant area under the receiver operating curve (AUC-ROC) (0.70,p= 0.013). GD subjects showed stronger PIT-related functional connectivity between NAcc and amygdala elicited by gambling cues, as well as between amygdala and OFC elicited by negative and positive cues. HC and GD subjects were thus distinguishable by PIT-related neural signatures including amygdala-NAcc-OFC functional connectivity. Neural PIT alterations in addictive disorders might not depend on the physiological effect of a substance of abuse but on related learning processes or even innate neural traits

The role of the Amygdala in the perception of reward

This study set out to examine the role of the amygdala in a number of appetitively motivated tasks. Experiment one was a position discrimination task with reversals, which in later reversals involved manipulation of some secondary reinforcers associated with a correct response, and the introduction of a magnitude of reward component. Rats with NMDA-induced amygdala lesions performed at a similar level to shams at the initial discrimination and first three reversals, proceeding to reverse faster than controls in the subsequent three reversals. Manipulation of secondary reinforcers led to an equal and significant decline in performance for both groups, with the lesioned animals retaining their significant superiority in reversal performance. Alteration of the task from a 2 vs 0 pellet discrimination to a 2 vs 1 led to a drastic increase in task difficulty, but both groups completed three reversals and did not differ significantly in performance. Experience of handling the lesioned animals led to the confirmation, in experiment two, that they were significantly more hostile/reactive to handling than shams (using die "blind" ratings of experienced animal handlers). Experiment three attempted to refine die picture of this behavioural change by measuring gross activity levels - no differences between groups were found. The finding of enhanced reversal performance and the absence of a magnitude of reward deficit amongst lesioned animals in experiment one were unanticipated, problematic and demand replication. No strong support was provided for either of the principal contemporary theories of amygdala involvement in secondary reinforcement. Increased reactivity to handling was found to be consistent with a minority of the past literature, and activity levels were as anticipated. It is argued that the notion of "stimulus-reward associations" as an amygdala function is incoherent and unhelpful, and that references to the functions of the amygdale as a whole rather than of subnuclei can be equally misleading

Autobiographisches Gedächtnis, der Einfluss von frühkindlichem Stress und neuronalen Korrelaten

Vandekerckhove M. Autobiographical memory begins and ends with the self : autobiographical memory, consciousness, the influence of stress and neural correlates. Bielefeld (Germany): Bielefeld University; 2004.The general purpose of this thesis is to study some fundamental, yet still open questions about autobiographical memory and related consciousness, the influence of early stress on the brain and autobiographical memory and its neural correlates. The goal is to make some progress in the definitory confusion and conceptual understanding of the relationship of these concepts starting from a developmental point of view. In the attempt to throw some light on what can fall under the sum of autobiographical memory-related themes, no overview or review of the existing answers will be given but rather, after extended research of the theoretical and empirical literature and own empirical work, a new clarifying point of view of the different phenomena. Considering the close relationship between the experience of the world, consciousness and autobiographical memory, the first question that becomes addressed in the theoretical part is how a child develops autobiographical memory and what Tulving entitles as associated "autonoetic consciousness", a self-reflective mental state of awareness in time and space (Tulving, 1985; 2002). The second question is concerned with how early childhood can form the basal template in the buffering and facilitation of influences of stress on the brain and also on autobiographical memory, with psychogenic amnesia and altered autonoetic consciousness as a prototypical example. Autobiographical old memories are as a result of a high degree of anatomical interconnectivity and cognitive complexity most vulnerable to brain damage and other external and internal influences such as stress (Markowitsch, 1995; 1999; 2000; 2002; 2003; Tulving and Markowitsch, 1998). The second empirical part of the thesis is primarily focused on the fundamental research of autobiographic memory and its neural correlates. The different focuses within the chapters will bring up more questions for theoretical thinking and empirical research about the same complexity of which individuals are made of

Structural and functional brain abnormalities in children with subclinical depression

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Kainate receptor auxiliary subunits NETO1 and NETO2 in anxiety and fear-related behaviors

Anxiety disorders are the most prevalent mental illnesses in Europe, yet, their molecular basis is poorly understood. Unraveling the molecular mechanisms underlying the occurrence and maintenance of anxiety is crucial for effective drug development to treat anxiety disorders. In this thesis work, I focused on the NETO1 and NETO2 auxiliary proteins for kainate receptors (KARs) that tightly modulate the functional properties of the receptor. Because variants in KAR genes have been associated with psychiatric diseases in humans, and with anxiety-like behavior in mice, we hypothesized that NETO1 and NETO2 regulate anxiety through their modulation of KARs. Therefore, the aim of this thesis was to investigate the role of NETO1 and NETO2 in the regulation of anxiety and fear, and to evaluate their potential as novel treatment targets for anxiety disorders. To test our hypothesis, I first carried out a comprehensive behavioral screen of Neto1+/+, Neto1-/-, Neto2+/+ and Neto2-/- mouse anxiety-like and fear-related behaviors. We showed that neither NETO1 nor NETO2 regulated anxiety-like behavior in mice. However, Neto2-/- mice had reduced activity in novel environments without effect on locomotor activity in familiar environments, stress physiology or depression-like behaviors. In cued fear conditioning, Neto2-/- but not Neto1-/- mice had increased fear expression and delayed extinction. To establish the molecular and cellular mechanisms modulating the fear phenotype of the Neto2-/- mice, I investigated its expression pattern by in situ hybridization in the core fear network, composed of the medial prefrontal cortex, the amygdala and the hippocampus. Neto2 was widely expressed in all of these regions and in both excitatory and inhibitory neurons. Accordingly, the NETO2 protein was detectable in the same regions. We next established that in the synapses of these brain regions, the abundance of GLUK2/3 and GLUK5 KAR subunits was reduced 20–40% in the absence of NETO2. By focusing on the amygdala, the central brain region for the processing of fear-inducing stimuli and fear learning, we observed immature features of parvalbumin-expressing inhibitory neurons in Neto2-/- mice. Furthermore, we found a higher amplitude and frequency of miniature excitatory post-synaptic currents specifically in the basolateral amygdala, which is a critical brain region for fear memory consolidation. Concurrent with these results, dendritic spine density in thin dendrites was higher in Neto2-/- compared to Neto2+/+ mice. Taken together, these findings imply stronger glutamatergic synapses within the amygdala in the absence of NETO2. Finally, using the c-Fos immediate early gene as a marker for neuronal activation, we found increased activation of amygdala neurons in Neto2-/- compared to Neto2+/+ mice after fear acquisition. Higher activation of the amygdala may be related to stronger associative learning and be represented behaviorally by higher levels of fear expression during fear conditioning. To summarize, we showed that in the absence of NETO2, mice demonstrate higher conditioned fear expression and extinction delay suggestive of a higher overall conditionability, which is a symptom of posttraumatic stress disorder (PTSD). Furthermore, we established that neither Neto1 nor Neto2 is required for innate anxiety-like behaviors. We propose that the reduced KAR abundance at the synapses of Neto2-/- mice, together with the immaturity and increased excitability of the amygdala, and with the stronger activation of local circuits within the amygdala during fear acquisition underlie the higher conditionability and delayed fear extinction phenotype. Our findings suggest directions for future mechanistic studies on the role of NETO2 in fear conditionability. Taken together, this work showed for the first time that Neto2 is required for normal fear expression and conditioning, and that it modulates amygdala function during associative fear learning, findings with putative therapeutic significance for PTSD.Ahdistuneisuushäiriöt ovat yleisimpiä mielenterveyden häiriöitä, mutta niiden molekyylitason syntymekanismeista tiedetään vasta vähän. Näiden mekanismien selvittäminen on tärkeää henkilökohtaistettujen hoitomuotojen kehittämiseksi. Tässä väitöskirjatyössä tutkittiin NETO1- ja NETO2-proteiineja, jotka sitoutuvat kainaattireseptoreihin (KAR) ja säätelevät niiden toiminnallisia ominaisuuksia. Koska KAR:ien tietyt geenimuodot ovat ihmisellä yhdistetty psykiatrisiin sairauksiin ja hiirillä ahdistuneisuustyyppiseen käyttäytymiseen, hypoteesimme oli, että NETO1 ja NETO2 säätelevät ahdistuneisuutta KAR:ien välityksellä. Väitöskirjatyössä tutkimme NETO1:n ja NETO2:n roolia ahdistuneisuuden ja pelon säätelyssä, sekä mahdollisina uusina hoitokohteina ahdistuneisuushäiriöissä. Selvitimme ensin käyttäytymiskokein Neto1+/+-, Neto1-/--, Neto2+/+- sekä Neto2-/--hiirten ahdistustyyppistä- ja pelkokäyttäytymistä. Osoitimme, ettei Neto1 tai Neto2 säätele ahdistustyyppistä käyttäytymistä hiirellä. Neto2-/--hiirten aktiivisuus oli kuitenkin vähentynyt uudessa ympäristössä. Näiden hiirten aktiivisuus kotihäkissä oli normaalia, eikä niillä ollut muutoksia stressifysiologiassa tai masennustyyppisessä käyttäytymisessä. Testasimme sekä Neto1-/-- että Neto2-/--hiirten pelkoehdollistumista ehdolliseen ärsykkeeseen. Neto1-/--hiiret eivät eronneet verrokeista, mutta Neto2-/--hiirten pelkokäyttäytyminen oli voimakkaampaa ja pelkoehdollistumisen purkautuminen hitaampaa kuin verrokkihiirillä. Tutkimme seuraavaksi in situ hybridisaatiolla missä soluissa Neto2 ilmentyy aivojen pelkoverkostoon kuuluvilla aivoalueilla (mediaalinen etuotsalohko, mantelitumake ja aivoturso). Neto2 ilmentyi laajasti kaikilla näillä alueilla, sekä eksitoivissa että inhiboivissa hermosoluissa. Vastaavasti, NETO2-proteiini ilmentyi samoilla aivoalueilla. Seuraavaksi osoitimme, että NETO2:n puuttuessa näiden alueiden synapseissa GLUK2/3 ja GLUK5 KAR-alayksiköiden määrä väheni 20-40 %. Väitöskirjan toinen osatyö keskittyi tutkimaan mantelitumaketta, joka prosessoi pelkoärsykkeitä ja on tärkeä aivoalue pelko-oppimisessa. Tutkimme amygdalan parvalbumiinia ilmentävien hermosolujen ja perineuronaalisten verkostojen lukumäärää ja osoitimme, että näiden amygdalan erilaistumiseen yhdistettyjen markkereiden määrä oli muuttunut Neto2-/--hiirillä, viitaten siihen, että Neto2 säätelee amygdalan kypsymistä. Lisäksi havaitsimme, että näiden hiirten miniatyyrisilla eksitoivilla postsynaptisilla virroilla oli suurempi amplitudi sekä taajuus basolateraalisessa amygdalassa, joka säätelee pelkoon liittyvien muistijälkien konsolidaatiota. Näihin tuloksiin sopien, Neto2-/--hiirillä oli Neto2+/+-hiiriin verrattuna enemmän haarakkeita ohuissa tuojahaarakkeissa. Tuloksemme viittaavat siihen, että NETO2:n puute mantelitumakkeessa vahvistaa glutamatergisia synapseja. Käyttäen c-FOS-proteiinia hermosolujen aktiivisuuden markkerina, osoitimme, että pelkoon liittyvän muistijäljen muodostuminen liittyi voimakkaampaan mantelitumakkeen hermosolujen aktivoitumiseen Neto2-/-- kuin Neto2+/+-hiirillä. Mantelitumakkeen voimakkaampi aktivaatio voi liittyä vahvempaan assosiatiiviseen oppimiseen, ja se voi esiintyä käyttäytymistasolla voimakkaampana pelon ilmentymisenä pelkoehdollistumisen aikana. Osoitimme siis, että NETO2 tarvitaan normaaliin pelkoehdollistumiseen ja sen purkautumiseen. Molemmat ilmiöt liittyvät korkeampaan ehdollistettavuuteen, mikä on yksi traumaperäisen stressihäiriön oire. Lisäksi osoitimme, etteivät Neto1 tai Neto2 ole välttämättömiä luontaiselle ahdistustyyppiselle käyttäytymiselle. Esitämme, että Neto2-/--hiirten pelkoehdollistumisfenotyyppi johtuu sekä kainaattireseptorien alhaisemmasta määrästä pelkoa säätelevillä aivoalueilla, että erityisesti amygdalan kehityksen ja toiminnan häiriöistä. Tämä väitöskirjatutkimus osoitti ensimmäisenä, että Neto2 tarvitaan normaaliin pelkokäyttäytymiseen ja –ehdollistumiseen, ja että se säätelee mantelitumakkeen toimintaa assosiatiivisessa pelko-oppimisessa. Nämä tulokset auttavat ymmärtämään traumaperäisen stressihäiriön neurobiologisia mekanismeja ja voivat olla avuksi uusien hoitomuotojen kehittämisessä

Recent Advances in Drug Addiction Research and Clinical Applications

Although it is well-accepted that drug addiction is a major public health concern, how we address it as a society continues to evolve as recent advances in the lab and clinic clarify the nature of the problem and influence our views. This unique collection of eight chapters reviews key findings on the neurobiology and therapeutics of addiction while capturing the diversity of perspectives that shape these concepts, which range from evolutionary biology to psychiatry to the legal system. This book discusses in depth how technological advances have led to important discoveries and how these discoveries, in turn, are increasingly being translated into clinical practice. It also presents avenues for future study that hold promise for the many affected by addiction