Differential transcriptome expression in human nucleus accumbens as a function of loneliness.

Loneliness is associated with impaired mental and physical health. Studies of lonely individuals reported differential expression of inflammatory genes in peripheral leukocytes and diminished activation in brain reward regions such as nucleus accumbens, but could not address gene expression in the human brain. Here, we examined genome-wide RNA expression in post-mortem nucleus accumbens from donors (N=26) with known loneliness measures. Loneliness was associated with 1710 differentially expressed transcripts and genes from 1599 genes (DEGs; false discovery rate P<0.05, fold change ⩾|2|, controlling for confounds) previously associated with behavioral processes, neurological disease, psychological disorders, cancer, organismal injury and skeletal and muscular disorders, as well as networks of upstream RNA regulators. Furthermore, a number of DEGs were associated with Alzheimer's disease (AD) genes (that was correlated with loneliness in this sample, although gene expression analyses controlled for AD diagnosis). These results identify novel targets for future mechanistic studies of gene networks in nucleus accumbens and gene regulatory mechanisms across a variety of diseases exacerbated by loneliness.

Genetics of emotion regulation.

Emotions can be powerful drivers of behavior that may be adaptive or maladaptive for the individual. Thus, the ability to alter one's emotions, to regulate them, should be beneficial to an individual's success of survival and fitness. What is the biological basis of this ability? And what are the biological mechanisms that impart individual differences in the ability to regulate emotion? In this article, we will first introduce readers to the construct of emotion regulation, and the various strategies that individuals may utilize to regulate their emotions. We will then point to evidence that suggests genetic contributions (alongside environmental contributions) to individual differences in emotion regulation. To date, efforts to identify specific genetic mechanisms involved in emotion regulation have focused on common gene variants (i.e. variants that exist in >1% of the population, referred to as polymorphisms) and their association with specific emotion regulation strategies or the neural substrate mediating these strategies. We will discuss these efforts, and conclude with a call to expand the set of experimental paradigms and putative molecular mechanisms, in order to significantly advance our understanding of the molecular mechanisms by which genes are involved in emotion regulation.

Amygdala responsiveness is modulated by tryptophan hydroxylase-2 gene variation.

The tryptophan hydroxylase-2 gene (TPH2) codes for the enzyme of serotonin (5-HT) synthesis in the brain and variation of TPH2 has been implicated in disorders of emotion regulation. Here, we used functional magnetic resonance imaging (fMRI) to demonstrate that a potentially functional variant of TPH2 modulates amygdala responsiveness to emotional stimuli of both negative and positive valence.

An fMRI study of personality influences on brain reactivity to emotional stimuli.

Functional imaging studies have examined which brain regions respond to emotional stimuli, but they have not determined how stable personality traits moderate such brain activation. Two personality traits, extraversion and neuroticism, are strongly associated with emotional experience and may thus moderate brain reactivity to emotional stimuli. The present study used functional magnetic resonance imaging to directly test whether individual differences in brain reactivity to emotional stimuli are correlated with extraversion and neuroticism in healthy women. Extraversion was correlated with brain reactivity to positive stimuli in localized brain regions, and neuroticism was correlated with brain reactivity to negative stimuli in localized brain regions. This study provides direct evidence that personality is associated with brain reactivity to emotional stimuli and identifies both common and distinct brain regions where such modulation takes place.

Event-related activation in the human amygdala associates with later memory for individual emotional experience.

The role of the amygdala in enhancing declarative memory for emotional experiences has been investigated in a number of animal, patient, and brain imaging studies. Brain imaging studies, in particular, have found a correlation between amygdala activation during encoding and subsequent memory. Because of the design of these studies, it is unknown whether this correlation is based on individual differences between participants or within-subject variations in moment-to-moment amygdala activation related to individual stimuli. In this study, participants saw neutral and negative scenes and indicated how emotionally intense they found each scene. Separate functional magnetic resonance imaging responses in the amygdala for each scene were related to the participants' report of their experience at study and to performance in an unexpected memory test 3 weeks after scanning. The amygdala had the greatest response to scenes rated as most emotionally intense. The degree of activity in the left amygdala during encoding was predictive of subsequent memory only for scenes rated as most emotionally intense. These findings support the view that amygdala activation reflects moment-to-moment subjective emotional experience and that this activation enhances memory in relation to the emotional intensity of an experience.

Hemispheric asymmetry for emotional stimuli detected with fMRI.

Current brain models of emotion processing hypothesize that positive (or approach-related) emotions are lateralized towards the left hemisphere, whereas negative (or withdrawal-related) emotions are lateralized towards the right hemisphere. Brain imaging studies, however, have so far failed to document such hemispheric lateralization. In a functional magnetic resonance imaging (fMRI) study, 14 female subjects viewed alternating blocks of emotionally valenced positive and negative pictures. When the experience of valence was equated for arousal, overall brain reactivity was lateralized towards the left hemisphere for positive pictures and towards the right hemisphere for negative pictures. This study provides direct support for the valence hypothesis, under conditions of equivalent arousal, by means of functional brain imaging.

Conditioned enhancement of the early component of the rat eyeblink reflex.

Conditioned enhancement of the rat eyeblink reflex was studied using as a response measure the electromyogram (EMG) in the orbicularis oculi (oo) muscle, which is responsible for the active force generating eyelid closure. During a reflex eyeblink, the EMG evidences both a short-latency (R1) and a long-latency (R2) component, mediated by different circuits. The R2 response exhibits several experience- or use-dependent modifications. We were interested in the modifiability of the neurophysiologically simpler R1 response. Experiments were designed to determine whether the R1 response can be enhanced by a conditioned stimulus (CS) that has been explicitly paired with an aversive unconditioned stimulus (US). The R1 response was elicited by electrical stimulation of the supraorbital branch of the trigeminal nerve. Following long-delay conditioning, the CS produced a significant R1 enhancement and latency decrease that were dependent upon explicit CS-US pairings. The CS by itself produced no significant EMG response, consistent with a modulatory rather than additive effect. This is the first demonstration that the R1 response can be associatively modulated. Based on other evidence, we hypothesize that the CS-produced enhancement results from a relatively direct projection from the amygdala to the R1 circuit. As an index of aversive conditioning, R1 enhancement may prove to be a useful expression system because it offers high temporal resolution and the underlying circuitry is relatively simple-the shortest path from the fifth nerve to the muscle consisting of only two central synapses.

Amygdala stimulation enhances the rat eyeblink reflex through a short-latency mechanism.

Amygdala stimulation was shown to enhance the trisynaptic (fast, R1) component of the electromyogram recorded in the rat orbicularis oculi (oo) muscle, which is responsible for the active force generating eyelid closure. The eyeblink was elicited via direct electrical stimulation of the supraorbital branch of the trigeminal nerve. Possible mechanisms responsible for the effect of amygdala stimulation on the eyeblink reflex were evaluated by measuring the amount of R1 enhancement as a function of the interstimulus interval (ISI) between the onset of amygdala and trigeminal nerve stimulation. Amygdala stimulation produced significant R1 enhancement at ISIs that imply short-latency excitation of the eyeblink circuit by way of a fast-acting neurotransmitter.

Conditioned diminution of the unconditioned response in rabbit eyeblink conditioning: identifying neural substrates in the cerebellum and brainstem.

Several models of Pavlovian conditioning assume that processing of an unconditioned stimulus (US) is diminished by a conditioned stimulus (CS) with which it had been paired. Two experiments evaluated the hypothesis that US processing may be diminished by CS-dependent activation of the cerebellum. Experiment 1 showed that electrical brain stimulation (EBS) of the cerebellar interpositus nucleus diminished the peak amplitude of the rabbit's unconditioned eyeblink response. This effect was bilateral, was systematically related to the intensity of EBS, maximal 50 ms after the offset of EBS, and substantially reversed by naloxone. Experiment 2 showed that inactivating the contralateral red nucleus with gamma-D-glutamylglycine blocked the decremental effect of interpositus stimulation. Implications for neural systems mediating the inhibitory effects of cerebellar activation and the antinociceptive role of noradrenergic and opioid systems in Pavlovian conditioning phenomena are discussed.

Potentiation or diminution of discrete motor unconditioned responses (rabbit eyeblink) to an aversive pavlovian unconditioned stimulus by two associative processes: conditioned fear and a conditioned diminution of unconditioned stimulus processing.

In two experiments using the rabbit conditioned eyeblink preparation, the conditions under which a Pavlovian conditioned stimulus (CS) potentiates or diminishes the unconditioned response (UR) were examined. The results indicated that, after discrimination training (CS+ vs. CS-), the CS+ diminished UR amplitude at the training interstimulus interval (ISI). When CS+ trials were segregated into trials on which a conditioned response (CR) did or did not occur, the CS+ diminished the UR when it elicited a CR, but not when a CR failed to occur. When the CS-unconditioned stimulus (US) interval was lengthened to 10 s, the CS+ reliably potentiated the eyeblink UR on CR trials but did not potentiate responding on trials on which a CR was absent. The results are discussed in terms of the modulatory effects and temporal properties of conditioned fear and an associatively produced decrement in US processing.

Opiate antagonists enhance the working memory of rats in the radial maze.

Two experiments tested the influence of the opiate antagonists naloxone and naltrexone on the spatial working memory of rats in a 12-arm radial maze. In Experiment 1, ten rats were serially forced to visit six randomly selected arms, then were removed from the maze for delays of either 30, 60, or 240 minutes, and then returned to the maze for a free-choice memory test with all 12 arms available. Five minutes into the delay, rats were injected intraperitoneally (IP) with either physiological saline or naloxone (1 mg/kg). When injected with naloxone the rats revisited forced-choice arms less often than when injected with saline during a subsequent free-choice test. In Experiment 2, twelve rats showed a similar facilitation of working memory when injected with the opiate antagonists naltrexone (0.3 mg/kg) and naloxone (1 mg/kg) in comparison to a saline control condition. These findings demonstrate the beneficial effects that opiate antagonists exert on working memory-based performance in the radial maze. They may also resolve conflicting reports about the influence of opiate antagonists on radial maze performance, by suggesting that the choice of measurement and testing conditions are crucial for detecting these effects in working memory procedures.