Dopamine is critically important in the neural manifestation of motivated behavior, and alterations in the human dopaminergic system have been implicated in the etiology of motivation-related psychiatric disorders, most prominently addiction. Patients with chronic addiction exhibit reduced dopamine D2 receptor (DRD2) availability in the striatum, and the DRD2 TaqIA (rs1800497) and C957T (rs6277) genetic polymorphisms have previously been linked to individual differences in striatal dopamine metabolism and clinical risk for alcohol and nicotine dependence. Here, we investigated the (...) hypothesis that the variants of these polymorphisms would show increased reward-related memory formation, which has previously been shown to jointly engage the mesolimbic dopaminergic system and the hippocampus, as a potential intermediate phenotype for addiction memory. To this end, we performed functional magnetic resonance imaging (fMRI) in 62 young, healthy individuals genotyped for DRD2 TaqIA and C957T variants. Participants performed an incentive delay task, followed by a recognition memory task 24 h later. We observed effects of both genotypes on the overall recognition performance with carriers of low-expressing variants, namely TaqIA A1 carriers and C957T C homozygotes, showing better performance than the other genotype groups. In addition to the better memory performance, C957T C homozygotes also exhibited a response bias for cues predicting monetary reward. At the neural level, the C957T polymorphism was associated with a genotype-related modulation of right hippocampal and striatal fMRI responses predictive of subsequent recognition confidence for reward-predicting items. Our results indicate that genetic variations associated with DRD2 expression affect explicit memory, specifically for rewarded stimuli. We suggest that the relatively better memory for rewarded stimuli in carriers of low-expressing DRD2 variants may reflect an intermediate phenotype of addiction memory. (shrink)

A social network is a web that integrates multiple levels of interindividual social relationships and has direct associations with an individual’s health and well-being. Previous research has mainly focused on how brain and social network structures act on each other and on how the brain supports the spread of ideas and behaviors within social networks. The structure of the social network is correlated with activity in the amygdala, which links decoding and interpreting social signals and social values. The structure also (...) relies on the mentalizing network, which is central to an individual’s ability to infer the mental states of others. Network functional properties depend on multilayer brain-social networks, indicating that information transmission is supported by the default mode system, the valuation system, and the mentalizing system. From the perspective of neuroendocrinology, overwhelming evidence shows that variations in oxytocin, β-endorphin and dopamine receptor genes, including oxytocin receptor, mu opioid receptor 1 and dopamine receptor 2, predict an individual’s social network structure, whereas oxytocin also contributes to improved transmission of emotional and behavioral information from person to person. Overall, previous studies have comprehensively revealed the effects of the brain, endocrine system, and genes on social networks. Future studies are required to determine the effects of cognitive abilities, such as memory, on social networks, the characteristics and neural mechanism of social networks in mental illness and how social networks change over time through the use of longitudinal methods. (shrink)

Several attempts have been made previously to provide a biological grounding for cognitive architectures by relating their components to the computations of specific brain circuits. Often, the architecture's action selection system is identified with the basal ganglia. However, this identification overlooks one of the most important features of the basal ganglia—the existence of a direct and an indirect pathway that compete against each other. This characteristic has important consequences in decision-making tasks, which are brought to light by Parkinson's disease as (...) well as genetic differences in dopamine receptors. This paper shows that a standard model of action selection in a cognitive architecture cannot replicate any of these findings, details an alternative solution that reconciles action selection in the architecture with the physiology of the basal ganglia, and extends the domain of application of cognitive architectures. The implication of this solution for other architectures and existing models are discussed. (shrink)

Women do most of the parenting. To provide a stable and healthier setting for children they must sublimate their own interests and feelings, which puts greater pressures on women to communicate needs clearly or to be deceptive when the occasion demands. The likely advantage in communication skills and self-control may ameliorate the impact of disorders like ADHD where the most serious deficit is in self-inhibition. This would account for the strikingly uneven male to female sex ratio of 2:1 (in epidemiological (...) samples) to 10:1 (in clinical settings), the higher threshold for females, and the sex difference in the pattern of associated mental disorders. (shrink)

Different anesthetics are known to modulate different types of membrane-bound receptors. Their common mechanism of action is expected to alter the mechanism for consciousness. Consciousness is hypothesized as the integral of all the units of internal sensations induced by reactivation of inter-postsynaptic membrane functional LINKs during mechanisms that lead to oscillating potentials. The thermodynamics of the spontaneous lateral curvature of lipid membranes induced by lipophilic anesthetics can lead to the formation of non-specific inter-postsynaptic membrane functional LINKs by different mechanisms. (...) These include direct membrane contact by excluding the inter-membrane hydrophilic region and readily reversible partial membrane hemifusion. The constant reorganization of the lipid membranes at the lateral edges of the postsynaptic terminals (dendritic spines) resulting from AMPA receptor-subunit vesicle exocytosis and endocytosis can favor the effect of anesthetic molecules on lipid membranes at this location. Induction of a large number of non-specific LINKs can alter the conformation of the integral of the units of internal sensations that maintain consciousness. Anesthetic requirement is reduced in the presence of dopamine that causes enlargement of dendritic spines. Externally applied pressure can transduce from the middle ear through the perilymph, cerebrospinal fluid, and the recently discovered glymphatic pathway to the extracellular matrix space, and finally to the paravenular space. The pressure gradient reduce solubility and displace anesthetic molecules from the membranes into the paravenular space, explaining the pressure reversal of anesthesia. Changes in membrane composition and the conversion of membrane hemifusion to fusion due to defects in the checkpoint mechanisms can lead to cytoplasmic content mixing between neurons and cause neurodegenerative changes. The common mechanism of anesthetics presented here can operate along with the known specific actions of different anesthetics. (shrink)

Depue & Morrone-Strupinsky (D&M-S) present a thorough case for the role of “reward” brain circuits in affiliative bonding. Integration of information in the nucleus accumbens shell (NA), the role of dopamine in this processing, and opioid (primarily via mu receptors) control of these circuits are the primary elements of the model. Although the overall picture is quite compelling, the description leans excessively in the view of dopamine systems as “reward” circuits.

The target article offers an important cautionary note on the interpretation of the heritability index. However, it does not directly address how culture and genes might interact. Here, we suggest that one allele of the dopamine D4 receptor gene promotes the acquisition of cultural values and practices and likely has coevolved with the human culture over the last 50,000 years.

Current research on the neural basis of consciousness is based mainly on neuroimaging, physiology and psychophysics. This target article reviews what is known about biochemical factors that may contribute to the development of consciousness, based on loss of consciousness (i.e., coma). There are two theories of the biochemical mode of action of general anaesthetics. One is that anaesthesia is a direct (i.e., not receptor-mediated) effect of the anaesthetic on cellular neurophysiological function; the other is that some alteration of receptor function (...) occurs. General anaesthetics are mainly GABA agonists but some (such as ketamine) are glutamate antagonists. They also affect other systems, particularly cholinergic ones. There are various comas of metabolic origin. For example, a combination of small doses of the iron chelators desferrioxamine and prochlorperazine induce a profound and long lasting coma in humans. The mechanisms that might mediate this include redox mechanisms at the glutamate synapse, post-synaptic endocytosis of dopamine and iron, and intracellular iron-dopamine complexes, which are powerful dismuters of the superoxide anion. New findings in cell biology relating to endocytosis and recycling of receptors are discussed in a wider context. These biochemical events may induce coma by two mechanisms: (i) Consciousness may depend on widespread cortical (or cortico-thalamic) activation. (ii) Whereas these biochemical changes are widespread, only the changes in a subset of consciousness' neurons may count. An experimental program to distinguish between these two alternatives is proposed. (shrink)

The Protein Ontology provides terms for and supports annotation of species-specific protein complexes in an ontology framework that relates them both to their components and to species-independent families of complexes. Comprehensive curation of experimentally known forms and annotations thereof is expected to expose discrepancies, differences, and gaps in our knowledge. We have annotated the early events of innate immune signaling mediated by Toll-Like Receptor 3 and 4 complexes in human, mouse, and chicken. The resulting ontology and annotation data set has (...) allowed us to identify species-specific gaps in experimental data and possible functional differences between species, and to employ inferred structural and functional relationships to suggest plausible resolutions of these discrepancies and gaps. (shrink)

This essay selectively reviews, from an historical and philosophical perspective, the dopamine (DA) hypothesis of schizophrenia (DHS; Table 1 lists the abbreviations used in this essay). Our goal is not to adjudicate the validity of the theory—although we arrive at a generally skeptical conclusion—but to focus on the process whereby the DHS has evolved over time and been evaluated. Since its inception, the DHS has been the most prominent etiologic theory in psychiatry and is still referred to widely in (...) current textbooks (e.g., Buchanan and Carpenter, Jr. 2005, 1336; Cohen 2003, 225; Gazzaniga 2004, 1257;Kandel et al. 2000, 1200). Understanding its origins and evolution should help to clarify the nature of modern .. (shrink)

Molecular vibrations and quantum tunneling may link ligand binding to the function of pharmacological receptors. The well‐established lock‐and‐key model explains a ligand's binding and recognition by a receptor; however, a general mechanism by which receptors translate binding into activation, inactivation, or modulation remains elusive. The Vibration Theory of Olfaction was proposed in the 1930s to explain this subset of receptor‐mediated phenomena by correlating odorant molecular vibrations to smell, but a mechanism was lacking. In the 1990s, inelastic electron tunneling (...) was proposed as a plausible mechanism for translating molecular vibration to odorant physiology. More recently, studies of ligands’ vibrational spectra and the use of deuterated ligand analogs have provided helpful information to study this admittedly controversial hypothesis in metabotropic receptors other than olfactory receptors. In the present work, based in part on published experiments from our laboratory using planarians as an experimental organism, I will present a rationale and possible experimental approach for extending this idea to ligand‐gated ion channels. (shrink)

Disruptions in dopamine transmission within the basal ganglia (BG) produce deficits in voluntary actions, that is, in the interface between cortically-generated goal representation and BG-mediated response selection. Under conditions of dopamine loss in humans and other animals, responses are impaired when they require internal generation, but are relatively intact when elicited by external stimuli.

Progress in solving the structure of insulin bound to its receptor has been slow and stepwise, but a milestone has now been reached with a refined structure of a complex of insulin with a “microreceptor” that contains the primary binding site. The insulin receptor is a dimeric allosteric enzyme that belongs to the family of receptor tyrosine kinases. The insulin binding process is complex and exhibits negative cooperativity. Biochemical evidence suggested that insulin, through two distinct binding sites, crosslinks two receptor (...) sites located on each α subunit. The structure of the unliganded receptor ectodomain showed a symmetrical folded‐over conformation with an antiparallel disposition. Further work resolved the detailed structure of receptor site 1, both without and with insulin. Recently, a missing piece in the puzzle was added: the C‐terminal portion of insulin's B‐chain known to be critical for binding and negative cooperativity. Here I discuss these findings and their implications. (shrink)

Kendler and Schaffner have written an exemplary case study of the rise of the dopamine hypothesis and, if not its fall, at least its stagnation and transmutation. They bring out well both the state of the science and the opportunities offered by the theory to consider some famous philosophical theories of scientific progress. So well, in fact, have they done this, that I do not have a lot to say about it. I will just mention one or two points (...) that I found interesting, and then say a little about what looks to me like an omission from the story that the two Kens recount.One point they raise is the importance of competitor theories: now, there is supposed to be an old story about a quack who was apprehended during .. (shrink)

The majority of G protein-coupled receptors (GPCRs) self-assemble in the form dimeric/oligomeric complexes along the plasma membrane. Due to the molecular interactions they participate, GPCRs can potentially provide the framework for discriminating a wide variety of intercellular signals, as based on some kind of combinatorial receptor codes. GPCRs can in fact transduce signals from the external milieu by modifying the activity of such intracellular proteins as adenylyl cyclases, phospholipases and ion channels via interactions with specific G-proteins. However, in spite (...) of the number of cell functions they can actually control, both GPCRs and their associated signal transduction pathways are extremely well conserved, for only a few alleles with null or minor functional alterations have so far been found. This would seem to suggest that, beside a mechanism for DNA repairing, there must be another level of quality control that may help maintaining GPCRs rather stable throughout evolution. We propose here receptor oligomerization to be a basic molecular mechanism controlling GPCRs redundancy in many different cell types, and the plasma membrane as the first hierarchical cell structure at which selective categorical sensing may occur. Categorical sensing can be seen as the cellular capacity for identifying and ordering complex patterns of mixed signals out of a contextual matrix, i.e., the recognition of meaningful patterns out of ubiquitous signals. In this context, redundancy and degeneracy may appear as the required feature to integrate the cell system into functional units of progressively higher hierarchical levels. (shrink)

Sensitivity to incentive motivation has a formative influence on extraversion. Mesoamygdaloid dopamine (DA) activity may, at one level, act as a micro-gate permitting an incentive to influence behavioral organization – “Go/No-Go” in this scheme. Data on function elsewhere in the mesocorticolimbic DA system are taken to support this particular function. At another level of analysis, the data in Depue & Collins's review, along with those on the rest of the ventral tegmental area (VTA) system, may fit better with a (...) “switching” function in information processing. This link is supported by correlations between measures of extraversion, learned inattention, and overall DA activity. The point is extended to the novelty-seeking feature of the extraverted personality. (shrink)

Depue & Collins's general idea of a functional relationship between DA activity and extraversion is an important step toward an integrative biological model of personality. However, focusing primarily on incentive motivation and variations in VTA DA activity as basic behavioral and biological components underlying extraversion appears too limited. Existing data suggest that responsivity to changes in DA activity is higher in introverts than in extraverts. This may reflect a general, extraversion- related characteristic of the entire dopaminergic network in the brain.

Depue & Collins propose that extraversion should be separated from the impulsivity-constraint dimension of personality, and that the VTA dopamine system is the primary engine of extraversion. Although their focus is on personality traits, it may be useful to consider the evidence on psychological state changes, related both to affective arousal and to drug effects. This evidence shows that there are inherent relations between extraversion and impulsivity-constraint, and that there are influences of dopamine on impulsivity-constraint that are not (...) consistent with the Depue & Collins model. Increased positive affect leads to increased extraversion, and this is associated with more impulsivity and less constraint. The evidence on drug effects shows that greater dopaminergic control is associated with more constraint, and with anxiety and vigilance rather than positive affect. (shrink)

Impaired performance in verbal fluency tasks is a frequent observation in Parkinson’s disease. As to the nature of the underlying cognitive deficit, it is commonly attributed to a frontal-type dysexecutive syndrome due to nigrostriatal dopamine depletion. Whereas dopaminergic medication typically improves VF performance in PD, e.g., by ameliorating impaired lexical switching, its effect on semantic network activation is unclear. Data from priming studies suggest that dopamine causes a faster decay of semantic activation spread. The aim of the current (...) study was to examine the impact of dopaminergic medication on the dynamic change of word frequency during VF performance as a measure of semantic spreading activation. To this end, we performed a median split analysis of word frequency during phonemic and semantic VF task performance in a PD group tested while receiving dopaminergic medication as well as after drug withdrawal, and in a sample of age-matched healthy volunteers. Dopaminergic medication in the PD group significantly affected phonemic VF with improved word production as well as increased error-rates. The expected decrease of word frequency during VF task performance was significantly smaller in the PD group ON medication than in healthy volunteers across semantic and phonemic VF. No significant group-difference emerged between controls and the PD group in the OFF condition. The comparison between both treatment conditions within the PD group did not reach statistical significance. The observed pattern of results indicates a faster decay of semantic network activation during lexical access in PD patients on dopaminergic medication. In view of improved word generation, this finding is consistent with a concept of more focused neural activity by an increased signal-to-noise ratio due to dopaminergic neuromodulation. However, the effect of dopaminergic stimulation on VF output suggests a trade-off between these beneficial effects and increased error-rates. (shrink)

Interpreting VTA dopamine activity as a facilitator of affective engagement fits Depue & Collins's agency dimension of extraverted personality and also Watson's and Tellegen's (1985) engagement dimension of state mood. Serotonin, by turning down the gain on dopaminergic affective engagement, would permit already prepotent responses or habits to prevail against the behavior-switching incentive-simulation-driven temptations of the moment facilitated by fickle VTA DA. Intelligent switching between openly responsive affective engagement and constraint by long-term plans, goals, or values presumably involves environment-sensitive (...) balancing of these neuromodulators, such as socially dominant primates may show. (shrink)

Estrogen receptor α (ERα) is a ligand‐dependent transcription factor that regulates the expression of estrogen‐responsive genes. Approximately 70% of patients with breast cancer are ERα positive. Estrogen stimulates cancer cell proliferation and contributes to tumor progression. Endocrine therapies, which suppress the ERα signaling pathway, significantly improve the prognosis of patients with breast cancer. However, the development of de novo or acquired endocrine therapy resistance remains a barrier to breast cancer treatment. Therefore, understanding the regulatory mechanisms of ERα is essential to (...) overcome the resistance to treatment. This review focuses on the regulation of ERα expression, including copy number variation, epigenetic regulation, transcriptional regulation, and stability, as well as functions from the point of view post‐translational modifications. (shrink)

The effects of striatal dopamine (DA) on behavior have been widely investigated over the past decades, with “phasic” burst firings considered as the key expression of a reward prediction error responsible for reinforcement learning. Less well studied is “tonic” DA, where putative functions include the idea that it is a regulator of vigor, incentive salience, disposition to exert an effort and a modulator of approach strategies. We present a model combining tonic and phasic DA to show how different outflows (...) triggered by either intrinsically or extrinsically motivating stimuli dynamically affect the basal ganglia by impacting on a selection process this system performs on its cortical input. The model, which has been tested on the simulated humanoid robot iCub interacting with a mechatronic board, shows the putative functions ascribed to DA emerging from the combination of a standard computational mechanism coupled to a differential sensitivity to the presence of DA across the striatum. (shrink)

New findings point to a role for mesolimbic DA circuits in the generation of dreaming. We disagree with Solms about these structures having an exclusive role in generating dreams. We review data suggesting that dreaming can be interrupted at different levels of processing and that anterior-subcortical lesions associated with dream cessation are unlikely to produce selective hypodopaminergic dynamic impairments. [Hobson et al.; Nielsen; Solms].

Whether or not trait affiliation correlates with human behaviour needs investigating. One should be careful generalizing neuropsychological mechanisms for affiliation, and generalizing an analysis based on one or two neuropsychological mechanisms and mostly studies on rodents, to complex human social interactions. Serotonin is an example of a neurotransmitter playing an important role in cooperation and interacting with the dopaminergic system.

Patients with schizophrenia have an impairment in the inhibition of reflexive saccades, as a consequence of a functional impairment of the prefrontal cortex, which has not yet been encapsulated in terms of a formal model. A number of novel and testable hypotheses can be generated from the framework proposed by Findlay & Walker that will stimulate further research. Their framework therefore marks an important step in the development of a comprehensive functional model of saccadic eye movements. Further advances will be (...) assisted by (1) a recognition of important distinctions in the executive control of volitional saccades and (2) addressing the capacity for cross-model integration of spatial information in the generation of the spatial properties of saccadic eye movements. (shrink)

We propose that the primary cause of schizophrenia is a pathological extension of synaptic pruning involving local connectivity that unfolds ordinarily during adolescence. Computer simulations suggest that this pathology provides reasonable accounts of a range of symptoms in schizophrenia, and is consistent with recent postmortem and genetic studies. NMDA-receptors play a regulatory role in maintaining and/or eliminating cortical synapses, and therefore may play a pathophysiological role.

Plasma membranes are subject to continuous deformations. Strikingly, some of these transient membrane undulations yield membrane‐associated signaling hubs that differ in composition and function, depending on membrane geometry and the availability of co‐factors. Here, recent advancements on this ubiquitous type of receptor‐independent signaling are reviewed, with a special focus on emerging concepts and technical challenges associated with studying these elusive signaling sites.