Serotonin mediates a learned increase in attraction to high concentrations of benzaldehyde in aged C. elegans

We utilized olfactory-mediated chemotaxis in Caenorhabditis elegans to examine the effect of aging on information processing and animal behavior. Wild-type (N2) young adults (day 4) initially approach and eventually avoid a point source of benzaldehyde. Aged adult animals (day 7) showed a stronger initial approach and a delayed avoidance to benzaldehyde compared with young adults. This delayed avoidance is due to an increased attraction rather than a decreased avoidance to benzaldehyde because (1) aged odr-3 mutants that are defective in odor attraction showed no delayed benzaldehyde avoidance, and (2) the delay in avoidance was also observed with another attractant diacetyl, but not the repellent octanol. Interestingly, the stronger expression of attractive behavior was only observed at benzaldehyde concentrations of 1% or higher. When worms were grown on nonbacterial growth media instead of Escherichia coli, thus removing the contingency between odors released from the food and the food itself, the increase in attraction to benzaldehyde disappeared. The increased attraction recovered after reinitiating the odor-food contingency by returning animals to E. coli food or supplementing axenic media with benzaldehyde. Moreover, serotonin-deficient mutants showed a deficit in the age-enhanced attraction. These results suggest that the increased attraction to benzaldehyde in aged worms is (1) serotonin mediated, (2) specific to high concentration of odorants, and (3) dependent on a learned association of odor metabolites with the presence of food. We propose that associative learning may selectively modify pathways at or downstream from a low-affinity olfactory receptor.     

Monogeusia for fructose,glucose, sucrose,and maltose

We investigated the ability of subjects to discriminate sugars with a whole-mouth forced-choice paradigm, in which a standard solution was compared with a test solution of varied concentration. Discrimination probabilities were U-shaped functions of test concentration: for 6 subjects and pairwise combinations of fructose, glucose, and sucrose, discriminability always declined to chance over a narrow range of test concentrations. At concentrations ≦ 100 mM, maltose was indiscriminable from fructose but discriminable at higher concentrations for 4 subjects. By analogy with themonochromacy of night vision, whereby any two lights are indiscriminable when their relative intensities are suitably adjusted, we call the gustatory indiscriminability of these sugarsmonogeusia. The simplest account of monogeusia is that all information about the indiscriminable sugars is represented by a single neural signal that varies only in magnitude. The discriminability of maltose from the other sugars at higher concentrations is consistent with the hypothesis that maltose also activates a second gustatory code.     

Constraints on decision making: Implications from genetics, personality, and addiction

An influential neurocomputational theory of the biological mechanisms of decision making, the “basal ganglia go/no-go model,” holds that individual variability in decision making is determined by differences in the makeup of a striatal system for approach and avoidance learning. The model has been tested empirically with the probabilistic selection task (PST), which determines whether individuals learn better from positive or negative feedback. In accordance with the model, in the present study we examined whether an individual’s ability to learn from positive and negative reinforcement can be predicted by genetic factors related to the midbrain dopamine system. We also asked whether psychiatric and personality factors related to substance dependence and dopamine affect PST performance. Although we found characteristics that predicted individual differences in approach versus avoidance learning, these observations were qualified by additional findings that appear inconsistent with the predictions of the go/no-go model. These results highlight a need for future research to validate the PST as a measure of basal ganglia reward learning.     

Analyses of habituation in Caenorhabditis elegans

Although the nonassociative form of learning, habituation, is often described as the simplest form of learning, remarkably little is known about the cellular processes underlying its behavioral expression. Here, we review research on habituation in the nematode Caenorhabditis elegans that addresses habituation at behavioral, neural circuit, and genetic levels. This work highlights the need to understand the dynamics of a behavior before attempting to determine its underlying mechanism. In many cases knowing the characteristics of a behavior can direct or guide a search for underlying cellular mechanisms. We have highlighted the importance of interstimulus interval (ISI) in both short- and long-term habituation and suggested that different cellular mechanisms might underlie habituation at different ISIs. Like other organisms, C. elegans shows both accumulation of habituation with repeated training blocks and long-term retention of spaced or distributed training, but not for massed training. Exposure to heat shock during the interblock intervals eliminates the long-term memory for habituation but not the accumulation of short-term habituation over blocks of training. Analyses using laser ablation of identified neurons, and of identified mutants have shown that there are multiple sites of plasticity for the response and that glutamate plays a role in long-term retention of habituation training.     

Changes in plasma corticosterone and cerebral biogenic amines and their catabolites during training and testing of mice in passive avoidance behavior

Concentrations of cerebral biogenic amines and their catabolites, and of plasma corticosterone were determined 10 min after training and testing of passive avoidance behavior in mice. Training and testing of mice that had acquired the task well resulted in statistically significant increases of plasma corticosterone, of the DOPAC:DA ratio [an index of dopamine (DA) metabolism] in prefrontal cortex, and of MHPG:NE ratios [an index of norepinephrine (NE) metabolism] in hypothalamus and brain stem. There were also decreases of NE in hypothalamus and brain stem, and an increase of 5-HIAA:5-HT [an index of serotonin (5-HT) metabolism] and of tryptophan in brain stem. Some of these changes also occurred in mice merely exposed to the apparatus but not trained. Plasma corticosterone concentrations were significantly higher in mice that performed the task well compared to those that did not, and there were significant correlations between this measure and the avoidance performance. Although there was only one statistically significant correlation between a cerebral metabolite and the avoidance performance (a decrease in hypothalamic NE), there were indications of relationships between cerebral biogenic amine metabolism and the performance. The patterns of neurochemical and endocrine changes closely resemble those previously observed in response to various stressors. Thus, the changes could reflect stress responses, which may or may not be related directly to the performance of the avoidance task.     

Behavioral effects of neurotoxic lesions of the ascending monoamine pathways in the rat brain

Intracranial microinjections of 6-hydroxydopamine or 5,6-dihydroxytryptamine into six ascending monoamine pathways produced the expected patterns of depletion of telencephalic serotonin, dopamine, and norepinephrine. Serotonin level was specifically lowered after dorsal or median raphe lesions but not after mesolimbic or nigrostriatal system lesions which lowered both norepinephrine and dopamine. Lesions in the locus coeruleus or ventral nor-adrenergic bundle lowered only norepinephrine, and locus coeruleus lesions elevated serotonin level. Behavior was examined in an open field, one-way active avoidance, and two passive avoidance tasks, and measures were taken of water consumption and body weight. Dorsal raphe lesions had no effect on any of the measures; the other five lesion groups exhibited deficient acquisition of the one-way active avoidance task. In the appetitive passive avoidance task, only the substantia nigra lesion group exhibited a deficiency. In the step-through passive avoidance task, both the substantia nigra and the median raphe groups exhibited a deficit, with the median raphe group exhibiting hyperactivity in the start box during testing. Water consumption was decreased by lesions in the ventral noradrenergic bundle during the first postoperative week and was increased in the median raphe group by the fourth postoperative week. Lastly, lesions in the locus coeruleus dramatically decreased activity in the open field. The results are discussed in regard to the search for specificity of behavioral functions of the distinct ascending monoamine pathways.     

Learning and memory deficits in mice lacking protease activated receptor-1

The roles of serine proteases and protease activated receptors have been extensively studied in coagulation, wound healing, inflammation, and neurodegeneration. More recently, serine proteases have been suggested to influence synaptic plasticity. In this context, we examined the role of protease activated receptor 1 (PAR1), which is activated following proteolytic cleavage by thrombin and plasmin, in emotionally motivated learning. We were particularly interested in PAR1 because its activation enhances the function of NMDA receptors, which are required for some forms of synaptic plasticity. We examined several baseline behavioral measures, including locomotor activity, expression of anxiety-like behavior, motor task acquisition, nociceptive responses, and startle responses in C57Bl/6 mice in which the PAR1 receptor has been genetically deleted. In addition, we evaluated learning and memory in these mice using two memory tasks, passive avoidance and cued fear-conditioning. Whereas locomotion, pain response, startle, and measures of baseline anxiety were largely unaffected by PAR1 removal, PAR1-/- animals showed significant deficits in a passive avoidance task and in cued fear conditioning. These data suggest that PAR1 may play an important role in emotionally motivated learning.     

Palatability shift of a salt-associated incentive during sodium depletion

Previous studies of natural palatability-sensitive reactions, elicited from rats by tastes, have indicated that the taste of concentrated NaCl becomes more palatable during states of body sodium depletion. A training procedure based upon “sensory preconditioning” or “irrelevant incentive” designs was used here to establish gustatory conditioned labels (quinine or citric acid) for either NaCl or fructose while rats were in a normal physiological state. Experiment 1 replicated demonstrations by others that gustatory conditioned labels for salt can attract and act as independent incentives during the salt appetite induced by sodium depletion. Experiment 2 used the taste reactivity measure to show that the enhanced palatability of the taste of NaCl transfers to produce enhanced palatability of the taste of the isolated conditioned label for salt in a state-dependent fashion. These results offer further support for the proposition that conditioned incentives not only predict hedonic events to follow, but themselves become attributed with the hedonic properties of their reinforcers.     

Learning to avoid in older age

The dopamine hypothesis of aging suggests that a monotonic dopaminergic decline accounts for many of the changes found in cognitive aging. The authors tested 44 older adults with a probabilistic selection task sensitive to dopaminergic function and designed to assess relative biases to learn more from positive or negative feedback. Previous studies demonstrated that low levels of dopamine lead to avoidance of those choices that lead to negative outcomes, whereas high levels of dopamine result in an increased sensitivity to positive outcomes. In the current study, age had a significant effect on the bias to avoid negative outcomes: Older seniors showed an enhanced tendency to learn from negative compared with positive consequences of their decisions. Younger seniors failed to show this negative learning bias. Moreover, the enhanced probabilistic integration of negative outcomes in older seniors was accompanied by a reduction in trial-to-trial learning from positive outcomes, thought to rely on working memory. These findings are consistent with models positing multiple neural mechanisms that support probabilistic integration and trial-to-trial behavior, which may be differentially impacted by older age.     

Intrusion, avoidance, and daily negative affect among couples coping with prostate cancer: a dyadic investigation

In the present study we examined how husbands' and wives' intrusive thoughts of prostate cancer (i.e., thinking about it when not meaning to) and avoidance (i.e., efforts to not think about cancer) related to their own and each other's average negative affect over a subsequent 14-day period. We examined whether congruence or similarity in intrusion about illness, but not avoidance, would be associated with less negative affect as this response to cancer could potentially facilitate adjustment. Fifty-nine husbands and wives completed measures of intrusion and avoidance after the diagnosis of prostate cancer and reported on their daily negative affect for 14 days. Using the actor-partner interdependence model, both patients and their wives who had high levels of intrusive thoughts experienced less negative affect when the other member of the couple also experienced high levels of intrusive thoughts. Those who had higher levels of avoidance had spouses who had higher levels of negative affect regardless of their own levels of avoidance. Congruence in responses to cancer may be adaptive for intrusion but not avoidance because the use of intrusive thoughts by both husbands and wives can allow couples to process the diagnosis of cancer, facilitating psychological adjustment, whereas avoidance does not. The current investigation adds to our understanding of how people within a marital dyad affect each other as they adjust to a cancer diagnosis.     

Serotonin: Modulator of a drive to withdraw

Serotonin is a fundamental neuromodulator in both vertebrate and invertebrate nervous systems, with a suspected role in many human mental disorders. Yet, because of the complexity of serotonergic function, researchers have been unable to agree on a general theory. One function suggested for serotonin systems is the avoidance of threat. We propose and review evidence for an alternative hypothesis, that a phylogenetically primitive of function of serotonin is to oppose the activating neuromodulators (particularly noradrenalin and dopamine). The functional effect of this opposition can be seen as applying a drive to withdraw from dangerous, aversive or high stimulation environments. Proposing that serotonin is involved in a drive to withdraw and seek contentment, instead of a drive to avoid, may be compatible with several lines of evidence on serotonin function and may facilitate a better understanding of serotonergic neuromodulation in human psychopathology.     

Serotonin: Modulator of a drive to withdraw

Serotonin is a fundamental neuromodulator in both vertebrate and invertebrate nervous systems, with a suspected role in many human mental disorders. Yet, because of the complexity of serotonergic function, researchers have been unable to agree on a general theory. One function suggested for serotonin systems is the avoidance of threat. We propose and review evidence for an alternative hypothesis, that a phylogenetically primitive of function of serotonin is to oppose the activating neuromodulators (particularly noradrenalin and dopamine). The functional effect of this opposition can be seen as applying a drive to withdraw from dangerous, aversive or high stimulation environments. Proposing that serotonin is involved in a drive to withdraw and seek contentment, instead of a drive to avoid, may be compatible with several lines of evidence on serotonin function and may facilitate a better understanding of serotonergic neuromodulation in human psychopathology.     

Beta-adrenergic receptor activation rescues theta frequency stimulation-induced LTP deficits in mice expressing C-terminally truncated NMDA receptor GluN2A subunits

Through protein interactions mediated by their cytoplasmic C termini the GluN2A and GluN2B subunits of NMDA receptors (NMDARs) have a key role in the formation of NMDAR signaling complexes at excitatory synapses. Although these signaling complexes are thought to have a crucial role in NMDAR-dependent forms of synaptic plasticity such as long-term potentiation (LTP), the role of the C terminus of GluN2A in coupling NMDARs to LTP enhancing and/or suppressing signaling pathways is unclear. To address this issue we examined the induction of LTP in the hippocampal CA1 region in mice lacking the C terminus of endogenous GluN2A subunits (GluN2AΔC/ΔC). Our results show that truncation of GluN2A subunits produces robust, but highly frequency-dependent, deficits in LTP and a reduction in basal levels of extracellular signal regulated kinase 2 (ERK2) activation and phosphorylation of AMPA receptor GluA1 subunits at a protein kinase A site (serine 845). Consistent with the notion that these signaling deficits contribute to the deficits in LTP in GluN2AΔC/ΔC mice, activating ERK2 and increasing GluA1 S845 phosphorylation through activation of β-adrenergic receptors rescued the induction of LTP in these mutants. Together, our results indicate that the capacity of excitatory synapses to undergo plasticity in response to different patterns of activity is dependent on the coupling of specific signaling pathways to the intracellular domains of the NMDARs and that abnormal plasticity resulting from mutations in NMDARs can be reduced by activation of key neuromodulatory transmitter receptors that engage converging signaling pathways.     

Case Study: A Quantitative Report of Early Attention,Fear, Disgust,and Avoidance in Specific Phobia for Buttons

Specific phobia is characterized by elevated early attention to the phobic object, negative emotion, and avoidance. Typically, phobic objects are biologically relevant, such as potentially threatening snakes or spiders, or potentially contaminating needles or rodents. It is unclear whether the same early attention, emotion, and avoidance responses can be observed in phobia for uncommon, nonbiologically relevant objects, such as buttons (koumpounophobia). In an experimental case study, we measured early attention (detection rates to briefly presented images before a backward mask), emotion, and avoidance to clothing buttons in a button-phobic participant. We compared these responses to nonphobic objects (zippers), and to well-matched control participants. We observed elevated early attention, fear, and disgust to buttons, which did not generalize to nonphobic emotional stimuli. In addition, we observed elevated avoidance of buttons, which did generalize to normatively fearful and disgusting pictures. If replicated, our results indicate that nonbiologically prepared phobic objects elicit similar elevated early attention, emotion, and avoidance as biologically prepared phobic objects. The finding that avoidance was the only response that generalized to nonphobic objects may have treatment implications—namely, that therapeutic attempts to reduce avoidance might consider including a variety of objects, not just the phobic object.     

Histidine-decarboxylase knockout mice show deficient nonreinforced episodic object memory, improved negatively reinforced water-maze performance, and increased neo- and ventro-striatal dopamine turnover

The brain's histaminergic system has been implicated in hippocampal synaptic plasticity, learning, and memory, as well as brain reward and reinforcement. Our past pharmacological and lesion studies indicated that the brain's histamine system exerts inhibitory effects on the brain's reinforcement respective reward system reciprocal to mesolimbic dopamine systems, thereby modulating learning and memory performance. Given the close functional relationship between brain reinforcement and memory processes, the total disruption of brain histamine synthesis via genetic disruption of its synthesizing enzyme, histidine decarboxylase (HDC), in the mouse might have differential effects on learning dependent on the task-inherent reinforcement contingencies. Here, we investigated the effects of an HDC gene disruption in the mouse in a nonreinforced object exploration task and a negatively reinforced water-maze task as well as on neo- and ventro-striatal dopamine systems known to be involved in brain reward and reinforcement. Histidine decarboxylase knockout (HDC-KO) mice had higher dihydrophenylacetic acid concentrations and a higher dihydrophenylacetic acid/dopamine ratio in the neostriatum. In the ventral striatum, dihydrophenylacetic acid/dopamine and 3-methoxytyramine/dopamine ratios were higher in HDC-KO mice. Furthermore, the HDC-KO mice showed improved water-maze performance during both hidden and cued platform tasks, but deficient object discrimination based on temporal relationships. Our data imply that disruption of brain histamine synthesis can have both memory promoting and suppressive effects via distinct and independent mechanisms and further indicate that these opposed effects are related to the task-inherent reinforcement contingencies.     

Lesions in the Central Nucleus of the Amygdala: Discriminative Avoidance Learning, Discriminative Approach Learning, and Cingulothalamic Training-Induced Neuronal Activity

The amygdala is critically involved in discriminative avoidance learning. Large lesions of the amygdala block discriminative avoidance learning and abolish cingulothalamic training-induced neuronal activity. These results indicated that amygdalar processing is critical for cingulothalamic plasticity. The larger lesions did not allow differentiation of the specific functioning of various amygdalar nuclei. Anatomical analysis showed that damage in the central (CE) nucleus of the amygdala was correlated with the severity of the behavioral deficit. The present study was carried out to determine whether smaller lesions, centered in the CE nucleus, would impair discriminative avoidance learning and block cingulothalamic plasticity. In addition, the possible role of the CE nucleus in appetitively motivated discriminative approach learning was examined for the first time. New Zealand White rabbits with CE nuclear lesions were first trained in the discriminative approach task. After attaining asymptotic performance, discriminative avoidance training sessions were alternated with continuing approach training sessions, one session each day. The rabbits with lesions were severely impaired in avoidance learning but showed no impairment of approach learning. Surprisingly, the attenuating effects of the lesions on cingulothalamic training-induced neuronal activity were more prevalent during approach learning than during avoidance learning. These results indicated that avoidance learning can be impaired by lesions centered in the CE nucleus that leave cingulothalamic plasticity largely intact and that the CE nucleus is involved in extra-cingulothalamic learning processes.     

Evolutionary and neuroendocrine foundations of human aggression

Humans present a behavioural paradox: they are peaceful in many circumstances, but they are also violent and kill conspecifics at high rates. We describe a social evolutionary theory to resolve this paradox. The theory interprets human aggression as a combination of low propensities for reactive aggression and coercive behaviour and high propensities for some forms of proactive aggression (especially coalitionary proactive aggression). These tendencies are associated with the evolution of groupishness, self-domestication, and social norms. This human aggression profile is expected to demand substantial plasticity in the evolved biological mechanisms responsible for aggression. We discuss the contributions of various social signalling molecules (testosterone, cortisol, oxytocin, vasopressin, serotonin, and dopamine) as the neuroendocrine foundation conferring such plasticity.     

Stress affects dopaminergic signaling pathways in Drosophila melanogaster

Behaviors modulated by dopamine appear to be conserved across species. In the model system Drosophila melanogaster, as in mammals, dopamine modulates female sexual receptivity, a simple form of learning and responses to drugs of abuse. Synthesis, reuptake and binding of dopamine are also evolutionarily conserved. Since stress has been shown to affect dopaminergic signaling pathways in mammals, we investigated the consequences of exposure to diverse stressors on dopaminergic physiology in the fruit fly, D. melanogaster. Animals were exposed to a metabolic stress (starvation), an oxidative stress (via the superoxide anion generator paraquat) or a mechanical stress (gentle vortexing). Sexual maturity, reproductive status, gender and type of stress differentially affected survival. The stress paradigms also resulted in alterations in the activity of tyrosine hydroxylase, the rate-limiting enzyme in dopamine biosynthesis. Exposure to these stressors perturbed female sexual receptivity and ovarian development, which are modulated by dopamine, suggesting that dopaminergic physiology is affected as a consequence of stress. Transgenic Drosophila with reduced levels of neuronal dopamine displayed an altered response to these stressors, suggesting that, as in mammals, dopamine is a key element in the stress response.     

Headache triggers: To avoid or not to avoid,that is the question

Abstract

Traditional clinical advice in the management of headaches is to avoid trigger factors. There is a danger, however, that avoidance of triggers results in a sensitisation process whereby tolerance for the triggers decreases, in a manner analogous to increments in anxiety arising from avoidance of anxiety-eliciting stimuli. Reported here are six single-case experiments in which the aim was to desensitise headache sufferers to an experimentally validated trigger, namely “visual disturbance”. The results demonstrated that repeated, prolonged exposure to a headache trigger led to desensitisation with participants experiencing less visual disturbance, less negative affect and less head pain in response to the trigger. These findings have theoretical significance as they speak to the issue of the aetiology of chronic headache, and practical significance as they suggest that a key aspect of current management may contribute to the disorder becoming worse rather than better.     

Role of the serotonin transporter gene in temperament and character

The biosocial model postulates that personality is comprised of two broad domains: temperament, which is largely due to inherited variations in specific monoamine neurotransmitter systems; and character, which arises from socioculturally learned differences in values, goals, and self-concepts and is the strongest predictor of personality disorders. The model also proposes that serotonin modulates the temperament trait of harm avoidance. We analyzed the association of temperament and character traits with the 5-HTTLPR, an inherited variation that modulates serotonin transporter gene expression, in 634 volunteer subjects. Contrary to theory, the 5-HTTLPR was most strongly associated with the character traits of cooperativeness and self-directedness. Associations with the temperament traits of reward dependence and harm avoidance were weaker and could be attributable largely to cross-correlations with the character traits and demographic variables. Psychometric analysis indicated that the serotonin transporter influences two broad areas of personality, negative affect and social disaffiliation, that are consistent across inventories but are more concisely described by the 5-factor model of personality than by the biosocial model. These results suggest that there is no fundamental mechanistic distinction between character and temperament in regard to the serotonin transporter gene, and that a single neurotransmitter can influence multiple personality traits.