The dopaminergic midbrain participates in human episodic memory formation: Evidence from genetic imaging

Recent data from animal studies raise the possibility that dopaminergic neuromodulation promotes the encoding of novel stimuli. We investigated a possible role for the dopaminergic midbrain in human episodic memory by measuring how polymorphisms in dopamine clearance pathways affect encoding-related brain activity (functional magnetic resonance imaging) in an episodic memory task. In 51 young, healthy adults, successful episodic encoding was associated with activation of the substantia nigra. This midbrain activation was modulated by a functional variable number of tandem repeat (VNTR) polymorphism in the dopamine transporter (DAT1) gene. Despite no differences in memory performance between genotype groups, carriers of the (low expressing) 9-repeat allele of the DAT1 VNTR showed relatively higher midbrain activation when compared with subjects homozygous for the 10-repeat allele, who express DAT1 at higher levels. The catechol-O-methyl transferase (COMT) Val108/158Met polymorphism, which is known to modulate enzyme activity, affected encoding-related activity in the right prefrontal cortex (PFC) and in occipital brain regions but not in the midbrain. Moreover, subjects homozygous for the (low activity) Met allele showed stronger functional coupling between the PFC and the hippocampus during encoding. Our finding that genetic variations in the dopamine clearance pathways affect encoding-related activation patterns in midbrain and PFC provides strong support for a role of dopaminergic neuromodulation in human episodic memory formation. It also supports the hypothesis of anatomically and functionally distinct roles for DAT1 and COMT in dopamine metabolism, with DAT1 modulating rapid, phasic midbrain activity and COMT being particularly involved in prefrontal dopamine clearance

The association between sleep-wake ratio and overnight picture recognition is moderated by BDNF genotype

A wealth of studies supports the role of sleep in memory performance. Experimentally controlled studies indicate that prolonged wake after memory encoding is detrimental for memory outcome whereas sleep protects from wake-time interference and promotes memory consolidation. We examined how the natural distribution of wake and sleep between encoding and retrieval associated with overnight picture recognition accuracy among 161 adolescents following their typical sleep schedule with an in-home polysomnography. The memorized pictures varied in their level of arousal (calm to exciting) and valence (negative to positive). Suspecting genotypic influence on the sensitivity for sleep/wake dynamics, we also assessed if these associations were affected by known gene polymorphisms involved in neural plasticity and sleep homeostasis: brain-derived neurotrophic factor (BDNF) Val66Met and Catechol‐O‐methyltransferase (COMT) Val158Met. In the whole sample, overnight recognition accuracy was associated with the levels of arousal and valence of the pictures, but not with sleep percentage (i.e. the percentage of time spent asleep between memory encoding and retrieval). While the allelic status of BDNF or COMT did not have any main effect on recognition accuracy, a significant moderation by BDNF Val66Met was found (p = .004): the subgroup homozygous for valine allele showed positive association between sleep percentage and recognition accuracy. This was underlain by detrimental influence of wake, rather than by any memory benefit of sleep. Our results complement the mounting evidence that the relation between sleep and memory performance is moderated by BDNF Val66Met. Further studies are needed to clarify the specific mechanisms.Peer reviewe

Prefrontal dopamine and the dynamic control of human long-term memory

Dopaminergic projections to the prefrontal cortex support higher-order cognitive functions, and are critically involved in many psychiatric disorders that involve memory deficits, including schizophrenia. The role of prefrontal dopamine in long-term memory, however, is still unclear. We used an imaging genetics approach to examine the hypothesis that dopamine availability in the prefrontal cortex selectively affects the ability to suppress interfering memories. Human participants were scanned via functional magnetic resonance imaging while practicing retrieval of previously studied target information in the face of interference from previously studied non-target information. This retrieval practice (RP) rendered the non-target information less retrievable on a later final test—a phenomenon known as retrieval-induced forgetting (RIF). In total, 54 participants were genotyped for the catechol-O-methyltransferase (COMT) Val108/158Met polymorphism. The COMT Val108/158Met genotype showed a selective and linear gene-dose effect on RIF, with the Met allele, which leads to higher prefrontal dopamine availability, being associated with greater RIF. Mirroring the behavioral pattern, the functional magnetic resonance imaging data revealed that Met allele carriers, compared with Val allele carriers, showed a greater response reduction in inhibitory control areas of the right inferior frontal cortex during RP, suggesting that they more efficiently reduced interference. These data support the hypothesis that the cortical dopaminergic system is centrally involved in the dynamic control of human long-term memory, supporting efficient remembering via the adaptive suppression of interfering memories

Oppositional COMT Val158Met effects on resting state functional connectivity in adolescents and adults

© 2014, The Author(s).Prefrontal dopamine levels are relatively increased in adolescence compared to adulthood. Genetic variation of COMT (COMT Val158Met) results in lower enzymatic activity and higher dopamine availability in Met carriers. Given the dramatic changes of synaptic dopamine during adolescence, it has been suggested that effects of COMT Val158Met genotypes might have oppositional effects in adolescents and adults. The present study aims to identify such oppositional COMT Val158Met effects in adolescents and adults in prefrontal brain networks at rest. Resting state functional connectivity data were collected from cross-sectional and multicenter study sites involving 106 healthy young adults (mean age 24 ± 2.6 years), gender matched to 106 randomly chosen 14-year-olds. We selected the anterior medial prefrontal cortex (amPFC) as seed due to its important role as nexus of the executive control and default mode network. We observed a significant age-dependent reversal of COMT Val158Met effects on resting state functional connectivity between amPFC and ventrolateral as well as dorsolateral prefrontal cortex, and parahippocampal gyrus. Val homozygous adults exhibited increased and adolescents decreased connectivity compared to Met homozygotes for all reported regions. Network analyses underscored the importance of the parahippocampal gyrus as mediator of observed effects. Results of this study demonstrate that adolescent and adult resting state networks are dose-dependently and diametrically affected by COMT genotypes following a hypothetical model of dopamine function that follows an inverted U-shaped curve. This study might provide cues for the understanding of disease onset or dopaminergic treatment mechanisms in major neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder

Neurocan genome-wide psychiatric risk variant affects explicit memory performance and hippocampal function in healthy humans

Alterations of the brain extracellular matrix (ECM) can perturb the structure and function of brain networks like the hippocampus, a key region in human memory that is commonly affected in psychiatric disorders. Here, we investigated the potential effects of a genome‐wide psychiatric risk variant in the NCAN gene encoding the ECM proteoglycan neurocan (rs1064395) on memory performance, hippocampal function and cortical morphology in young, healthy volunteers. We assessed verbal memory performance in two cohorts (N = 572, 302) and found reduced recall performance in risk allele (A) carriers across both cohorts. In 117 participants, we performed functional magnetic resonance imaging using a novelty‐encoding task with visual scenes. Risk allele carriers showed higher false alarm rates during recognition, accompanied by inefficiently increased left hippocampal activation. To assess effects of rs1064395 on brain morphology, we performed voxel‐based morphometry in 420 participants from four independent cohorts and found lower grey matter density in the ventrolateral and rostral prefrontal cortex of risk allele carriers. In silico eQTL analysis revealed that rs1064395 SNP is linked not only to increased prefrontal expression of the NCAN gene itself, but also of the neighbouring HAPLN4 gene, suggesting a more complex effect of the SNP on ECM composition. Our results suggest that the NCAN rs1064395 A allele is associated with lower hippocampus‐dependent memory function, variation of prefrontal cortex structure and ECM composition. Considering the well‐documented hippocampal and prefrontal dysfunction in bipolar disorder and schizophrenia, our results may reflect an intermediate phenotype by which NCAN rs1064395 contributes to disease risk

Human Aging Magnifies Genetic Effects on Executive Functioning and Working Memory

We demonstrate that common genetic polymorphisms contribute to the increasing heterogeneity of cognitive functioning in old age. We assess two common Val/Met polymorphisms, one affecting the Catechol-O-Methyltransferase (COMT) enzyme, which degrades dopamine (DA) in prefrontal cortex (PFC), and the other influencing the brain-derived neurotrophic factor (BDNF) protein. In two tasks (Wisconsin Card Sorting and spatial working memory), we find that effects of COMT genotype on cognitive performance are magnified in old age and modulated by BDNF genotype. Older COMT Val homozygotes showed particularly low levels of performance if they were also BDNF Met carriers. The age-associated magnification of COMT gene effects provides novel information on the inverted U-shaped relation linking dopaminergic neuromodulation in PFC to cognitive performance. The modulation of COMT effects by BDNF extends recent evidence of close interactions between frontal and medial-temporal circuitries in executive functioning and working memory

Sleep and its oscillatory characteristics in overnight learning : what is the role of plasticity genes BDNF and COMT?

Sleep is crucial for memory function. Sleep not only protects memories from wake-time interference, but it also actively transfers them from temporal storage to more permanent representations in the neocortex. This consolidation process of declarative memories is believed to be facilitated by certain oscillations during non-rapid eye movement (NREM) sleep, that is, sleep spindles, slow oscillations (SO) and sharp-wave ripples. Recent experiments in humans have demonstrated the importance of inter-oscillation synchrony on memory retention. Do all individuals equally share the memory benefits of sleep? Certain gene polymorphisms, such as BDNF Val66Met and COMT Val158Met, have been attributed with implications on synaptic plasticity, neuroanatomy and functional brain activation within memory-related brain networks. Behavioral studies have found relative mnemonic advantages to associate with the alleles that reportedly promote brain plasticity, i.e. ValBDNF and MetCOMT. Moreover, homeostatic sleep drive is moderated by BDNF Val66Met and COMT Val158Met. However, the role of these polymorphisms in memory retention over sleep has been scarcely studied. In this thesis, overnight memory for verbal and visual material was studied. Specific focus was put on how sleep spindles and their phasic synchrony with slow oscillations associate with memory performance. Importantly, it was questioned whether genetic predisposition for neural plasticity (BDNF Val66Met and COMT Val158Met) interacts with overnight memory and the related consolidation mechanisms. The studies in this thesis were conducted either on an adolescent (~17 y) cohort or on a sample consisting of young adults. Sleep was recorded with an ambulatory polysomnography in all studies. It was found that memory outcome – both verbal cued recall and picture recognition – was strongly associated with fast sleep spindles and their accurate coupling with the depolarized ‘upstate’ of SOs. BDNF Val66Met moderated the associations between sleep oscillations and visual recognition memory: memory outcome was robustly predicted by fast sleep spindles and their SO-coupling only in ValBDNF homozygotes but not MetBDNF carriers. In addition, memory performance in the ValBDNF homozygote group was seen more vulnerable to extended wake during the retention period. COMT Val158Met did not moderate the associations between sleep variables and recognition accuracy. In conclusion, the relation between sleep and memory may depend on inheritance. Genetic propensity for synaptic plasticity possibly enhances the effect of events that promote sleep-dependent consolidation. The findings question whether the benefits of sleep on memory are constant and equal across individuals.Uni on välttämätöntä muistin toiminnalle. Uni ei ainoastaan suojaa muistoja valveajan sekoittumiselta, vaan se myös aktiivisesti siirtää niitä väliaikaisesta muistivarastosta pysyviksi edustuksiksi aivokuorelle. Tiettyjen NREM-unen (non-rapid eye movement) aikaisten aivoaaltojen, eli unisukkuloiden, hitaiden aaltojen sekä hippokampusväreiden, uskotaan aktiivisesti edistävän tätä muistojen konsolidoitumista. Tutkimukset ihmisillä ovat osoittaneet, että aaltojen välinen synkronia on oleellista muistojen säilymiselle. Ovatko unen muistihyödyt yhtäläiset yksilöiden välillä? Tietyt geenipolymorfismit, kuten BDNF Val66Met ja COMT Val158Met, on aiemmassa tutkimuksessa yhdistetty aivoyhteyksien muovautuvuuteen, aivoanatomiaan sekä -toimintaan niissä rakenteissa, jotka tukevat muistitoimintoja. Alleelien, joiden oletetaan edistävän aivojen plastisuutta (ValBDNF ja MetCOMT), on käyttäytymisen tasolla havaittu assosioituvan suhteelliseen etuun muistisuoriutumisessa. Tämän lisäksi on raportoitu, että BDNF Val66Met sekä COMT Val158Met vaikuttavat unipaineen säätelyyn. Tästä huolimatta näiden polymorfismien roolia unen ja muistamisen yhteydessä on tutkittu vain vähän. Tämä väitöskirja tutki kielellistä ja näönvaraista muistamista yön yli. Erityisesti keskityttiin siihen, kuinka unisukkulat sekä niiden vaihesynkronia hitaiden aaltojen kanssa assosioituvat muistisuoriutumiseen. Lisäksi tarkasteltiin, onko perinnöllinen taipumus aivojen plastisuuteen (BDNF Val66Met ja COMT Val158Met) yhteydessä yön yli muistamiseen (näönvarainen tunnistus) ja unen aikaisiin konsolidaatiomekanismeihin. Väitöskirjan tutkimukset toteutettiin joko nuorista (~17 v) koostuvassa kohortissa tai nuorten aikuisten otoksessa. Genotyyppiin liittyvät tutkimukset koskivat nuorten otosta. Kaikissa tutkimuksissa unta mitattiin polysomnografialla. Muistitulos – sekä kielellinen, vihjeenvarainen muistaminen että kuvien tunnistus – oli selvästi yhteydessä unisukkuloihin sekä siihen, kuinka tarkasti unisukkulat ajoittuivat hitaisiin aaltoihin. BDNF Val66Met vaikutti aivoaaltojen ja näönvaraisen tunnistusmuistin yhteyksiin: yhteys ilmeni ainoastaan ValBDNF-homotsygooteilla, mutta ei MetBDNF-alleelin kantajilla. Lisäksi ValBDNF-homotsygooteilla runsas valve näytti haittaavan muistisuoriutumista. COMT Val158Met ei vaikuttanut unimuuttujien ja tunnistustarkkuuden yhteyksiin. Tulokset viittaavat siihen, että unen ja muistin yhteys saattaa jossain määrin riippua perimästä. Geneettinen taipumus aivoplastisuuteen saattaa voimistaa unen aikaisten konsolidaatiomekanismien vaikutusta. Tämä kyseenalaistaa ajatuksen siitä, että unen hyödyt olisivat muuttumattomat sekä jokaiselle yhtäläiset

Age-Related Decline in Brain Resources Modulates Genetic Effects on Cognitive Functioning

Individual differences in cognitive performance increase from early to late adulthood, likely reflecting influences of a multitude of factors. We hypothesize that losses in neurochemical and anatomical brain resources in normal aging modulate the effects of common genetic variations on cognitive functioning. Our hypothesis is based on the assumption that the function relating brain resources to cognition is nonlinear, so that genetic differences exert increasingly large effects on cognition as resources recede from high to medium levels in the course of aging. Direct empirical support for this hypothesis comes from a study by Nagel et al. (2008), who reported that the effects of the Catechol-O-Methyltransferase (COMT) gene on cognitive performance are magnified in old age and interacted with the Brain-Derived Neurotrophic Factor (BDNF) gene. We conclude that common genetic polymorphisms contribute to the increasing heterogeneity of cognitive functioning in old age. Extensions of the hypothesis to other polymorphisms are discussed. (150 of 150 words