Björn H. Schott

Reward-related fMRI activation of dopaminergic midbrain Is associated with enhanced hippocampus- dependent long-term memory formation

Long-term potentiation in the hippocampus can be enhanced and prolonged by dopaminergic inputs from midbrain structures such as the substantia nigra. This improved synaptic plasticity is hypothesized to be associated with better memory consolidation in the hippocampus. We used a condition that reliably elicits a dopaminergic response, reward anticipation, to study the relationship between activity of dopaminergic midbrain areas and hippocampal long-term memory in healthy adults. Pictures of object drawings that predicted monetary reward were associated with stronger fMRI activity in reward-related brain areas, including the substantia nigra, compared with non-reward-predicting pictures. Three weeks later, recollection and source memory were better for reward-predicting than for non-reward-predicting pictures. FMRI activity in the hippocampus and the midbrain was higher for reward-predicting pictures that were later recognized compared with later forgotten pictures. These data are consistent with the hypothesis that activation of dopaminergic midbrain regions enhances hippocampus-dependent memory formation, possibly by enhancing consolidation.

Mesolimbic Functional Magnetic Resonance Imaging Activations during Reward Anticipation Correlate with Reward-Related Ventral Striatal Dopamine Release

The dopaminergic mechanisms that control reward-motivated behavior are the subject of intense study, but it is yet unclear how, in humans, neural activity in mesolimbic reward-circuitry and its functional neuroimaging correlates are related to dopamine release. To address this question, we obtained functional magnetic resonance imaging (fMRI) measures of reward-related neural activity and [11C]raclopride positron emission tomography measures of dopamine release in the same human participants, while they performed a delayed monetary incentive task. Across the cohort, a positive correlation emerged between neural activity of the substantia nigra/ventral tegmental area (SN/VTA), the main origin of dopaminergic neurotransmission, during reward anticipation and reward-related [11C]raclopride displacement as an index of dopamine release in the ventral striatum, major target of SN/VTA dopamine neurons. Neural activity in the ventral striatum/nucleus accumbens itself also correlated with ventral striatal dopamine release. Additionally, high-reward-related dopamine release was associated with increased activation of limbic structures, such as the amygdala and the hippocampus. The observed correlations of reward-related mesolimbic fMRI activation and dopamine release provide evidence that dopaminergic neurotransmission plays a quantitative role in human mesolimbic reward processing. Moreover, the combined neurochemical and hemodynamic imaging approach used here opens up new perspectives for the investigation of molecular mechanisms underlying human cognition.

Delamination and detachment of a lithospheric root

Abstract Orogens can be formed by shortening of the lithosphere on time scales much shorter than that of thermal diffusion. For time scales of a few Ma, the major part of the uplift of an orogen, which may occur during the transition from crustal shortening to extension, may be due to delamination of the mantle lithosphere rather than to convective thinning. The negative buoyancy forces of a lithospheric root may cause lateral shortening, while the lithospheric root delaminates (peels off) from the crust, detaches, and is replaced by hot upwelling asthenosphere. This provides a large input of heat into the crust. Geological observations show that the late orogenic phase may be characterized by volcanic activity, high temperature–low pressure metamorphism, extension, high heat flow, and a rapid (within a few Ma) increase of the topography. We present dynamically and thermally consistent numerical models of the evolution of an orogenic root. Mantle rheology is based on laboratory data of olivine. While models with the rheology of olivine do not allow for delamination due to its very high viscosity, the incorporation of a quasi brittle rheology is necessary for modelling delamination of the mantle lithosphere. Successful delamination models are always associated with a rapid change in topography. We examined the parameter range of our models and found different regimes of behaviour of the orogenic root of the mantle lithosphere: no delamination, delamination, delamination and full detachment. For a fixed viscosity of the upper crust of 1023 Pa s delamination occurs for a range of viscosities of 1023 Pa s to 1020 Pa s for the lower crust, depending on the thickness of the lithospheric root. But full detachment of the delaminated lithospheric slab only occurs if the viscosity of the lower crust is greater than approximately 1021 Pa s. Hot asthenosphere is welling up into the gap opening during delamination. Further implications of our models are: Lithospheric roots or unsupported slabs of at least 100–170 km depth extent are needed to provide sufficient negative buoyancy to allow delamination and detachment. In all delamination models significant amounts of lower crustal material are subducted into the mantle. In applying our models to selected orogens we argue that mantle delamination may have played an important role in the Variscan and the Himalayan orogenies.

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.

Medial temporal theta state before an event predicts episodic encoding success in humans

We report a human electrophysiological brain state that predicts successful memory for events before they occur. Using magnetoencephalographic recordings of brain activity during episodic memory encoding, we show that amplitudes of theta oscillations shortly preceding the onsets of words were higher for later-recalled than for later-forgotten words. Furthermore, single-trial analyses revealed that recall rate in all 24 participants tested increased as a function of increasing prestimulus theta amplitude. This positive correlation was independent of whether participants were preparing for semantic or phonemic stimulus processing, thus likely signifying a memory-related theta state rather than a preparatory task set. Source analysis located this theta state to the medial temporal lobe, a region known to be critical for encoding and recall. These findings provide insight into state-related aspects of memory formation in humans, and open a perspective for improving memory through theta-related brain states.

Personality Traits Are Differentially Associated with Patterns of Reward and Novelty Processing in the Human Substantia Nigra/Ventral Tegmental Area

BACKGROUND The long-standing observation that the novelty-seeking personality trait is a predictor of drug use and other reinforcable risky behaviors raises the question as to how novelty and reward processing functionally interact in mesolimbic dopaminergic circuitry and how this interaction is modulated by the novelty-seeking personality trait. METHODS Functional magnetic resonance imaging (fMRI) hemodynamic responses to novelty and reward (monetary incentive) from the substantia nigra/ventral tegmental area (SN/VTA), the nucleus accumbens (NAcc), and the hippocampus of 29 subjects were correlated with novelty-seeking scores. These correlations were compared with those obtained for scores of reward-dependence. The fMRI data were taken from two experiments in which the interaction of novelty and reward was manipulated as a within-subject variable, and long-term memory for the critical stimuli was assessed after 24 hours. RESULTS Novelty-seeking was positively correlated with SN/VTA activation elicited by novel cues that did not predict reward, whereas reward-dependence was related to activations elicited by novel cues that predicted reward. The positive correlation between SN/VTA responses to novelty and novelty-seeking scores was accompanied by a negative correlation with reward-related SN/VTA activation and memory enhancement. CONCLUSIONS SN/VTA responses to novelty and reward are differentially affected by personality traits of novelty-seeking and reward-dependence. Importantly, novelty-seekers were more responsive to novel cues in the absence of reward and needed less reward to boost their memory for novel cues. These observations strongly suggest that for novelty-seekers, the motivational value of novelty is not necessarily based on actual reward-predicting stimulus properties.

Perceptual Priming Versus Explicit Memory: Dissociable Neural Correlates at Encoding

We addressed the hypothesis that perceptual priming and explicit memory have distinct neural correlates at encoding. Event-related potentials (ERPs) were recorded while participants studied visually presented words at deep versus shallow levels of processing (LOPs). The ERPs were sorted by whether or not participants later used studied words as completions to three-letter word stems in an intentional memory test, and by whether or not they indicated that these completions were remembered from the study list. Study trials from which words were later used and not remembered (primed trials) and study trials from which words were later used and remembered (remembered trials) were compared to study trials from which words were later not used (forgotten trials), in order to measure the ERP difference associated with later memory (DM effect). Primed trials involved an early (200450 msec) centroparietal negative-going DM effect. Remembered trials involved a late (9001200 msec) right frontal, positive-going DM effect regardless of LOP, as well as an earlier (600800 msec) central, positive-going DM effect during shallow study processing only. All three DM effects differed topographically, and, in terms of their onset or duration, from the extended (6001200 msec) fronto-central, positive-going shift for deep compared with shallow study processing. The results provide the first clear evidence that perceptual priming and explicit memory have distinct neural correlates at encoding, consistent with Tulving and Schacters (1990) distinction between brain systems concerned with perceptual representation versus semantic and episodic memory. They also shed additional light on encoding processes associated with later explicit memory, by suggesting that brain processes influenced by LOP set the stage for other, at least partially separable, brain processes that are more directly related to encoding success.

Recapitulating emotional context: activity of amygdala, hippocampus and fusiform cortex during recollection and familiarity

The amygdala is thought to enhance long‐term memory for emotionally arousing events by modulating memory formation and storage in the hippocampus and in neocortical areas. Recent animal studies have raised the possibility that cooperativity between amygdala and hippocampus contributes to the retrieval of fear memories. The functional contributions of the amygdala to the retrieval of emotional memories in humans are less well known. Here, in a functional magnetic resonance imaging experiment, 20 healthy subjects studied neutral words in the context of a fearful or a neutral human face. In a subsequent test, they made ‘remember’ (conscious recollection of the study context), ‘know’ (familiarity in the absence of conscious recollection) and ‘new’ judgements on the studied and newly presented neutral words, in the absence of face stimuli. At test, bilateral amygdala, hippocampus and fusiform face area (FFA) were more strongly activated during recollection than during familiarity. Higher activity for fearful than for neutral study context was found in bilateral FFA during recollection but not during familiarity. This difference recapitulated higher activity for fearful than for neutral context in the FFA during study. These data suggest that the amygdalae and hippocampi contribute to the retrieval of emotion‐laden context memories by coordinating the reactivation of stored representations in neocortical areas, such as the FFA. However, there also was a recapitulation of emotional study context in the right amygdala during familiarity only, which might therefore be related to affective implicit memory.

Neuroanatomical Dissociation of Encoding Processes Related to Priming and Explicit Memory

Priming is a facilitation of cognitive processing with stimulus repetition that can occur without explicit memory. Whereas the functional neuroanatomy of perceptual priming at retrieval is established, encoding processes that initiate priming and explicit memory have not yet been anatomically separated, and we investigated them using event-related functional magnetic resonance imaging. Activations predicting later explicit memory occurred in the bilateral medial temporal lobe (MTL) and left prefrontal cortex (PFC). Activity predicting later priming did not occur in these areas, but rather in the bilateral extrastriate cortex, left fusiform gyrus, and bilateral inferior PFC, areas linked with stimulus identification. Surprisingly, these regions showed response reductions. Our results demonstrate that priming and explicit memory have distinct functional neuroanatomies at encoding, with MTL activations being specific for explicit memory, and suggest that priming is initiated by sharpness of neural responding in stimulus identification areas, consistent with recent electrophysiological evidence regarding priming-related neural oscillations at encoding. We tentatively suggest that this sharpened responding at encoding may set the stage for increased neural processing efficiency at retrieval, with these different neural mechanisms both leading to observed priming-related hemodynamic decreases, and argue that neural measurements at encoding, and not just at retrieval, will be critical in resolving the debate about the neural mechanisms of learning that underlie priming.

Dopaminergic Modulation of Auditory Cortex-Dependent Memory Consolidation through mTOR

Previous studies in the auditory cortex of Mongolian gerbils on discrimination learning of the direction of frequency-modulated tones (FMs) revealed that long-term memory formation involves activation of the dopaminergic system, activity of the protein kinase mammalian target of rapamycin (mTOR), and protein synthesis. This led to the hypothesis that the dopaminergic system might modulate memory formation via regulation of mTOR, which is implicated in translational control. Here, we report that the D1/D5 dopamine receptor agonist SKF-38393 substantially improved gerbils’ FM discrimination learning when administered systemically or locally into the auditory cortex shortly before, shortly after, or 1 day before conditioning. Although acquisition performance during initial training was normal, the discrimination of FMs was enhanced during retraining performed hours or days after agonist injection compared with vehicle-injected controls. The D1/D5 receptor antagonist SCH-23390, the mTOR inhibitor rapamycin, and the protein synthesis blocker anisomycin suppressed this effect. By immunohistochemistry, D1 dopamine receptors were identified in the gerbil auditory cortex predominantly in the infragranular layers. Together, these findings suggest that in the gerbil auditory cortex dopaminergic inputs regulate mTOR-mediated, protein synthesis-dependent mechanisms, thus controlling for hours or days the consolidation of memory required for the discrimination of complex auditory stimuli.