Specialised information processing deficits and distinct metabolomics profiles following TM-domain disruption of Nrg1

While there is considerable genetic and pathologic evidence for an association between neuregulin 1 (NRG1) dysregulation and schizophrenia, the underlying molecular and cellular mechanisms remain unclear. Mutant mice containing disruption of the transmembrane (TM) domain of the NRG1 gene constitute a heuristic model for dysregulation of NRG1-ErbB4 signalling in schizophrenia. The present study focused on specialised behavioural and characterisation of hitherto un-characterised information processing phenotypes in this mutant line. Using a mass spectrometry-based metabolomics approach, we also quantified levels of unique metabolites in brain. Across two different sites and protocols, Nrg1 mutants demonstrated deficits in pre-pulse inhibition, a measure of sensorimotor gating that is disrupted in schizophrenia; these deficits were partially reversed by acute treatment with second-, but not first-, generation antipsychotic drugs. However, Nrg1 mutants did not show a specific deficit in latent inhibition, a measure of selective attention that is also disrupted in schizophrenia. In contrast, in the ‘what-where-when’ cognitive paradigm, Nrg1 mutants displayed sex-specific (males only) disruption of ‘what-when’ performance, indicative of impaired episodic memory. Differential metabolomic profiling revealed that these behavioural phenotypes were accompanied, most prominently, by alterations in lipid metabolism pathways. This study is the first to associate these novel physiological mechanisms, previously independently identified as being abnormal in schizophrenia, with disruption of NRG1 function. These data suggest novel mechanisms by which compromised neuregulin function from birth might lead to schizophrenia-relevant behavioural changes in adulthood

The role of dopamine D2 and neuregulin-1 receptors in schizophrenia relevant phenotypes of cognition, attention and memory

Aberrant neurotransmitter function promotes cognitive deficits in schizophrenia. These abnormalities in functioning are seen as disruptions in attentional and information processing, as well as disruptions in the consolidation and retrieval of information. Tasks of attentional salience and memory that are used to model these disruptions include the latent inhibition (LI) task of attentional salience, prepulse inhibition (PPI) task of sensorimotor gating and an Episodic memory (EM) task, which is an index of memory for episodes at a particular point in time. Aberrant functioning of candidate genes that are associated with risk for schizophrenia may be seen as behavioural alterations in these tasks of schizophrenia relevant phenotypes. dopaminergic hyperactivity and hypofunction have been implicated in mediating disruptions on these cognitive tasks. Increased transmission in the dopamine system in the striatal region promotes schizophrenia symptoms, and indirect dopamine (DA) agonist Amphetamine worsens these symptoms in patients, and disrupts schizophrenia relevant behaviours on these cognitive tasks. We investigated the effects of deletion of two genes relevant to schizophrenia on cognitive tasks known to be disrupted in the disorder. The effect of deletion of the dopamine D2 receptor (D2R) and trans membrane (TM) domain Neuregulin-1 (Nrg-1) receptor were investigated in mediating disruptions in cognitive processes in an animal model of schizophrenia. The role of the D2R in an attentional model of sensorimotor gating was assessed. PPI was attenuated in D2R knock out (KO), in a one day sensorimotor gating task. In a one day PPI test protocol, amphetamine disruptions on PPI were spared in D2R WT and KO mice. Following on from previous reports of disrupted LI by a single low dose amphetamine injection, separated by 24h interval, we established a single vs. two low dose PPI protocol in order to facilitate a direct comparison of amphetamine induced disruption in LI with PPI. A one injection (prior to test only) vs. two injection (prior to habituation and prior to test) task was established. In the two day protocol, a single low dose of amphetamine disrupted PPI in D2R KO mice and reduced startle reactivity to the 120 dB pulse alone trials. Two low dose injections of amphetamine however, do not disrupt PPI in D2R KO or their WT littermates, and do not mimic low dose amphetamine disruptions in the LI task. These findings demonstrate that prior conclusions about the requirement of the D2R for amphetamine effects in PPI does not generalise to all dose regimens. Episodic memory was also investigated as a measure of cognitive impairment in schizophrenia. D2R KO mice show sex specific dissociations on an EM task. Male D2R WT and KO animals show equal exploration of old vs. recent objects on the what-when component of the EM task, and female KO animals show enhanced memory for old vs. recent objects. Both D2R WT and KO mice show intact memory for displaced objects. These deficits were also investigated in the TM domain Nrg-1 model. Nrg-1 has been implicated as a candidate gene for schizophrenia, and behavioural phenotypes assessing its role in cognitive impairment in schizophrenia were established. Intact LI is seen in both Nrg-1 WT and Het animals. Nrg-1 TM domain Het mutants also show deficits on the schizophrenia relevant PPI task. Nrg-1 Het mutants show attenuated % PPI compared to their WT littermates, which reflects interrupted sensorimotor gating in schizophrenia. Lastly, we found some evidence that reduced function of TM-domain of the Nrg-1 gene disrupted episodic-like memory (what- where-when recognition) in males and improved it in females

The role of dopamine D2 and neuregulin-1 receptors in schizophrenia relevant phenotypes of cognition, attention and memory

Aberrant neurotransmitter function promotes cognitive deficits in schizophrenia. These abnormalities in functioning are seen as disruptions in attentional and information processing, as well as disruptions in the consolidation and retrieval of information. Tasks of attentional salience and memory that are used to model these disruptions include the latent inhibition (LI) task of attentional salience, prepulse inhibition (PPI) task of sensorimotor gating and an Episodic memory (EM) task, which is an index of memory for episodes at a particular point in time. Aberrant functioning of candidate genes that are associated with risk for schizophrenia may be seen as behavioural alterations in these tasks of schizophrenia relevant phenotypes. dopaminergic hyperactivity and hypofunction have been implicated in mediating disruptions on these cognitive tasks. Increased transmission in the dopamine system in the striatal region promotes schizophrenia symptoms, and indirect dopamine (DA) agonist Amphetamine worsens these symptoms in patients, and disrupts schizophrenia relevant behaviours on these cognitive tasks. We investigated the effects of deletion of two genes relevant to schizophrenia on cognitive tasks known to be disrupted in the disorder. The effect of deletion of the dopamine D2 receptor (D2R) and trans membrane (TM) domain Neuregulin-1 (Nrg-1) receptor were investigated in mediating disruptions in cognitive processes in an animal model of schizophrenia. The role of the D2R in an attentional model of sensorimotor gating was assessed. PPI was attenuated in D2R knock out (KO), in a one day sensorimotor gating task. In a one day PPI test protocol, amphetamine disruptions on PPI were spared in D2R WT and KO mice. Following on from previous reports of disrupted LI by a single low dose amphetamine injection, separated by 24h interval, we established a single vs. two low dose PPI protocol in order to facilitate a direct comparison of amphetamine induced disruption in LI with PPI. A one injection (prior to test only) vs. two injection (prior to habituation and prior to test) task was established. In the two day protocol, a single low dose of amphetamine disrupted PPI in D2R KO mice and reduced startle reactivity to the 120 dB pulse alone trials. Two low dose injections of amphetamine however, do not disrupt PPI in D2R KO or their WT littermates, and do not mimic low dose amphetamine disruptions in the LI task. These findings demonstrate that prior conclusions about the requirement of the D2R for amphetamine effects in PPI does not generalise to all dose regimens. Episodic memory was also investigated as a measure of cognitive impairment in schizophrenia. D2R KO mice show sex specific dissociations on an EM task. Male D2R WT and KO animals show equal exploration of old vs. recent objects on the what-when component of the EM task, and female KO animals show enhanced memory for old vs. recent objects. Both D2R WT and KO mice show intact memory for displaced objects. These deficits were also investigated in the TM domain Nrg-1 model. Nrg-1 has been implicated as a candidate gene for schizophrenia, and behavioural phenotypes assessing its role in cognitive impairment in schizophrenia were established. Intact LI is seen in both Nrg-1 WT and Het animals. Nrg-1 TM domain Het mutants also show deficits on the schizophrenia relevant PPI task. Nrg-1 Het mutants show attenuated % PPI compared to their WT littermates, which reflects interrupted sensorimotor gating in schizophrenia. Lastly, we found some evidence that reduced function of TM-domain of the Nrg-1 gene disrupted episodic-like memory (what- where-when recognition) in males and improved it in females

Medial Temporal Lobe Structure and Function

Medial Temporal Lobe Structure and Function by Meghana Sunil Karnik Doctor of Philosophy in Biology and Biomedical Sciences: Neuroscience) Washington University in St. Louis, 2009 Professor John G. Csernansky, Chairperson My main goal was to examine the relationship between brain structure and function, specifically medial temporal lobe structure and episodic memory, in various groups of subjects who had schizophrenia, were at risk for schizophrenia because of genetic and disease influences, or who were healthy, in order to explore the influence of genetic and disease influences on brain structure-function relationships. Most of what is known about the neural structures thought to subserve episodic memory has been gleaned from studies of experimental lesions in animals, traumatic brain injury in humans, functional activation in healthy individuals, and age-related changes in specific structure-function relationships. By comparison, there has been a paucity of research on the variability of normative structure-function relationships and how such relationships might be influenced by disease. In conducting this work, I began with the assumption that medial temporal lobe structure-function relationships would be influenced by genetic factors. Thus, I chose to study the relationship between medial temporal lobe structure and episodic memory performance in the context of a disease known to have a strong genetic basis, namely schizophrenia. Moreover, schizophrenia has been frequently associated with altered medial temporal lobe structure and deficits in episodic memory. In this project, I subdivided the medial temporal lobe into two structural groupings - the hippocampus and the parahippocampal gyrus: PHG) and its subregions: entorhinal cortex, perirhinal cortex, and parahippocampal cortex: ERC, PRC and PHC. respectively). The subdivision of the PHG into its subregions was novel, and required the development of new methods for cortical assessment and parcelation. The specific aims of this project were: 1. To collect cognitive data and high resolution MR scans in groups of individuals with schizophrenia, healthy controls, and their siblings. 2. To extract a measure of episodic memory performance by selecting measures from the cognitive testing that assesses episodic memory. 3. To make measurements of hippocampal volume and the volume and thickness of the parahippocampal gyrus and its subregions. 4. Using a combined database of cognitive and structural data, to examine the relationship between medial temporal lobe structure and episodic memory performance in health and disease

Modulation of Hippocampal-Prefrontal Circuitry During Spatial Working Memory

Spatial working memory (SWM) is an essential feature of goal-directed action. Locating a resource, a threat, or even oneself within a dynamic or unfamiliar environment requires a cached representation of relevant spatial features that must be continuously updated, preserved, and applied as needed to the execution of appropriate behaviors (Baddeley and Hitch 1974). SWM is disrupted in schizophrenia, as well as in multiple animal models of the disease. Patients with schizophrenia show impairment on tasks with both verbal and spatial working memory demands (Park and Holzman 1992, Conklin, Curtis et al. 2000) and exhibit abnormalities in neurophysiological signals that are associated with normal cognitive performance. More specifically, convergent data from diverse studies suggests that disruption of long-range functional connectivity may underlie diverse cognitive and physiological symptoms of the schizophrenia. It is therefore imperative that pathways of long-range functional connectivity that support the cognitive processes impaired in schizophrenia be identified and characterized, so that effective interventions can be targeted to the appropriate neural structures and pathways. Despite long-standing interest in the neurobiological underpinnings of working memory, its multiple cognitive components, distributed anatomical constituents, and distinct temporal phases have rendered its investigation elusive (Logie 1995, Miyake and Shah 1999, Andrade 2001, de Zubicaray, McMahon et al. 2001, Baddeley 2003, Klauer and Zhao 2004). Despite these challenges, an extensive body of work supports the idea that the prefrontal cortex (PFC) plays a central role in the successful execution of tasks requiring spatial working memory (Curtis and D'Esposito 2004). Moreover, the joint contribution of medial prefrontal cortex (mPFC) and hippocampus (HPC) supports successful spatial working memory in rodents (Lee and Kesner 2003, Jones and Wilson 2005, Wang and Cai 2006, Hyman, Zilli et al. 2010, Sigurdsson, Stark et al. 2010). It remains unclear, however, which phase(s) of SWM (encoding, maintenance, and/or retrieval) require the joint participation of HPC and mPFC, what behaviorally relevant information is conveyed between the two structures, and by what anatomical pathway(s) they interact. Although HPC and mPFC share multiple second-degree anatomical connections, including via striatum, amygdala, entorhinal cortex, and midline thalamic nuclei, direct connectivity between the two structures is confined to a unidirectional projection from the Ca1/subiculum of the ventral hippocampus (vHPC) to prelimbic (PL) and infralimbic (IL) regions of the mPFC (Jay and Witter 1991, Hoover and Vertes 2007, Oh 2014). Cells of both vHPC and mPFC exhibit location-specific firing that could function to encode spatial cues critical to SWM (Jung, Wiener et al. 1994, Poucet, Thinus-Blanc et al. 1994, Jung, Qin et al. 1998, Hok, Save et al. 2005, Kjelstrup, Solstad et al. 2008, Burton, Hok et al. 2009, Royer, Sirota et al. 2010, Keinath, Wang et al. 2014). Moreover, damage to the vHPC disrupts representations of salient locations in mPFC (Burton, Hok et al. 2009), suggesting that the vHPCmPFC projection may transmit SWM critical location information. We therefore tested the role of vHPC-mPFC afferents in spatial working memory using an a projection silencing approach that afforded anatomical and temporal precision and found that the vHPC-mPFC direct input is necessary for encoding, not maintenance or retrieval, of SWM-dependent cues. Combining this approach with in vivo extracellular recordings of mPFC single units, we found that location-selective firing in the mPFC during SWM is dependent on vHPC direct input exclusively during the encoding phase of each trial. Finally, we found evidence that the transmission of task-critical information in the vHPC-mPFC pathway is mediated by the synchronizing of mPFC cells to gamma oscillations in the vHPC. Together, these findings suggest a role for the vHPC-mPFC pathway in the encoding of cues critical to SWM and may indicate a potential locus of pathophysiological disruption underlying the cognitive impairments associated with schiziphrenia

Functional Investigations into the Recognition Memory Network, its Association with Genetic Polymorphisms and Implications for Disorders of Emotional Memory

Recent research, that has been focused on recognition memory, has revealed that two processes contribute to recognition of previously encountered items: recollection and familiarity (Aggleton & Brown, 1999; Eichenbaum, 2006; Eichenbaum, Yonelinas, & Ranganath, 2007; Rugg & Yonelinas, 2003; Skinner & Fernandes, 2007; Squire, Stark, & Clark, 2004; Wixted, 2007a; Yonelinas, 2001a; Yonelinas, 2002). The findings of neural correlates of recollection and familiarity lead to the assumption that there are different brain regions activated in either process, but there are, to the best of my knowledge, no studies assessing how these brain regions are working together in a recollection or a familiarity network, respectively. Additionally, there are almost no studies to date, which directly searched for overlapping regions. Therefore, in study I of the current thesis, brain regions associated to both recognition processes are searched investigated. Additionally, a connectivity analysis will search for functional correlated brain activations that either build a recollection or a familiarity network. It is undoubtable that the Brain Derived Neurotrophic Factor (BDNF) is strongly involved in synaptic plasticity in the hippocampus (Bramham & Messaoudi, 2005) and there is evidence that a genetic variant of this neurotrophin (BDNF 66Met) is related to poorer memory performance (Egan, et al., 2003). Therefore, in study II of the current thesis, the effect of BDNF Val66Met on recollection and familiarity performance and related brain activations is investigated. Finally, one could summarize, that serotonin, like BDNF, is strongly involved in brain development and plasticity as well as in learning and memory processes (Vizi, 2008). More precisely, there is evidence for alterations in the structure of brain regions, which are known to be involved in emotional memory formation and retrieval, like amygdala and hippocampus (Frodl, et al., 2008; Munafo, Brown, & Hariri, 2008; Pezawas, et al., 2005). One study found an slight epistatic effect of BDNF and 5-HTTLPR on the grey matter volume of the amygdala (Pezawas, et al., 2008). Therefore, in study III, it is investigated if such an interaction effect could be substantiated for the amygdala and additionally revealed for the hippocampus. The results of the current thesis allow further comprehension of recollection, hence episodic memory, and point to a special role of the BDNF in temporal and prefrontal brain regions. Additionally, the finding of an epistatic effect between BDNF and serotonin transporter function point to the need of analyzing interactions between genes and also between genes and environmental factors which reveals more information than the study of main effects alone. In conclusion, analyzing behavioral and neural correlates of episodic memory reveal allowed insights in brain functions that may serve as guideline for future studies in clinical populations with memory deficits, including susceptibility factors such as good or bad environment, as well as promising gene variants that influence episodic memory

The Genetics of Affective Cognition: Electrophysiological Evidence for Individual Differences in Affective Picture Processing, Attention and Memory

Affect and cognition have traditionally been considered mutually exclusive domains and their study has evolved into two separate research fields. In recent years, however, there is increasing evidence of affective modulations of cognitive processes and interest in the study of affective cognition has grown. This thesis presents analyses of data collected in four mixed-design experiments between 2009 and 2011, which were designed to investigate affective memory and its electrophysiological correlates, individual differences in said affective memory and electrophysiological correlates, the time-course of affective memory and attentional disengagement from affective stimuli respectively. The first aim of the research presented here was to further understanding of how affective content influences picture processing and memory. Event-related potentials (ERPs) provide a valuable tool for the investigation of modulations of cognitive processes, as their excellent temporal resolution allows for the dissociation between different processes contributing to behavioural outcomes. Several important results for the study of affective cognition are reported: The late positive potential (LPP) was shown to be modulated differentially by affective content when compared to a behavioural attentional disengagement task. While the behavioural measure of attention replicated findings from participants’ self-report of arousal, LPP enhancement did not. This novel finding demonstrates that the affective modulation of the LPP cannot be used as an electrophysiological marker of slowed attentional disengagement as is common in the literature. In the domain of recognition memory, affective modulation of performance was shown to be time-sensitive, with effects developing faster for negative than for positive picture content. Affective pictures were associated with a less conservative response bias than neutral pictures but only negative pictures elicited better discrimination performance, driven by an increased in the rate of “remembered” as compared to merely familiar pictures. This was reflected in an increase of the ERP old/new effect for negative pictures in the 500 to 800ms time window, the purported correlate of recollection. The late right-frontal old/new effect between 800 and 1500 ms post stimulus onset was shown to be attenuated by affective content, supporting the interpretation of the late right-frontal effect as a correlate of relevance detection over a retrieval success interpretation. In combination, the findings add weight to the conclusion that affective content enhances memory through selective memory sparing for affective stimuli. Novel evidence for gender differences in affective cognition was found. Comparisons between female and male participants revealed that the affective modulation of the late right-frontal effect differs between the genders, underlining the importance of assessing and understanding gender differences as part of the study of affective cognition. Brain-derived neurotrophic factor (BDNF) gene val66met single nucleotide polymorphism (SNP), a small genetic change that affects the functioning of BDNF, a protein that plays an important role in neuron growth, differentiation and survival, is shown here to also affect the interaction of affect and cognition. BDNF val66met genotype modulated the early “familiarity” old/new effect selectively in response to positive pictures. The present study clearly demonstrates the value of the ERP technique in the investigation of individual differences in affective and cognitive processing and the need to take such individual differences into account as part of the endeavour to fully understand the mechanisms of affective processing, cognition and affective cognition. A better understanding of the role of gender and genetic differences in the affective modulation of affective processing and memory will have important practical implications in fields where affect and cognition interact

Genetic influences on emotion/cognition interactions : from synaptic regulation to individual differences in working memory for emotional faces

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