A neuronal network switch for approach/avoidance toggled by appetitive state

Concrete examples of computation and implementation of cost/benefit decisions at the level of neuronal circuits are largely lacking. Such decisions are based on appetitive state, which is the integration of sensation, internal state, and memory. Value-based decisions are accessible in neuronal circuitry of simple systems. In one such system, the predatory sea slug Pleurobranchaea, appetite is readily quantified in behavior and related to approach/avoidance decision. Moreover, motor aspects of feeding and turning can be observed as fictive motor output in the isolated central nervous system (CNS). Here we found that the excitation state of the feeding motor network both manifested appetitive state and controlled expression of orienting versus avoidance. In isolated CNSs, spontaneous feeding network activity varied proportionally to donor feeding thresholds. CNSs from low- and high-feeding-threshold donors expressed fictive orienting or avoidance, respectively, in response to brief stimulation of sensory nerves. Artificially exciting the feeding network converted fictive avoidance to orienting. Thus, the feeding network embodied appetitive state and toggled approach/avoidance decision by configuring response symmetry of the premotor turn network. A resulting model suggests a basic cost/benefit decision module from which to consider evolutionary elaboration of the circuitry to serve more intricate valuation processes in complex animals.     

The Role of the Escape Swim Motor Network in the Organization of Behavioral Hierarchy and Arousal in Pleurobranchaea

The escape swimming pattern generator of the notaspid opisthobranchPleurobranchaea drives a high threshold, override behavior.The pattern generator is integrated with neural networks ofother behaviors so as to coordinate unitary behavioral expressionand to promote general behavioral arousal. These functions areseparately produced by different swim network elements. Oneset of swim premotor neurons, the A1/A10 ensemble, A3 and I_VS,generate the swim pattern and, through corollary activity, suppresspotentially conflicting feeding behavior by exerting broad inhibitionat major feeding network interneurons. A second set of swimneurons, the serotonergic As1–4 neurons, provides intrinsicneuromodulatory excitation to the swim pattern generator thatsustains the escape swim episode through multiple cycles. TheAs1–4 also provide neuromodulatory excitation to importantmodulatory, serotonergic cells in the feeding motor networkand locomotor network, and may have a general regulatory rolein the distributed serotonergic arousal network of the mollusk.The As1–4 appear to be also necessary to both avoidanceand orienting turning, and are therefore likely to be critical,multi-functional components upon which much of the organizationof the animal's behavior rests.     

Serotonin,Eating Behavior,and Fat Intake

There is an intimate relationship between nutritional intake (eating) and serotonin activity. Experimental manipulations (mainly neuropharmacological) of serotonin influence the pattern of eating behavior, subjective feelings of appetite motivation, and the response to nutritional challenges. Similarly, nutritional manipulations (food restriction, dieting, or altered nutrient supply) change the sensitivity of the serotonin network. Traditionally, serotonin has been linked to the macronutrient carbohydrate via the intermediary step of plasma amino acid ratios. However, it has also been demonstrated that 5-HT drugs will reduce energy intake and reverse body weight gain in rats exposed to weight increasing high fat diets. 5-HT drugs can also reduce food intake and block weight gain of rats on a high fat cafeteria diet. Some diet selection studies in rats indicate that the most prominent reduction of macronutrient intake is for fat. These data indicate that 5-HT activity can bring about a reduction in fat consumption. In turn, different types of dietary fat can alter brain 5-HT activity. In human studies the methodology of food choice experiments has often precluded the detection of an effect of 5-HT manipulation on fat intake. However, there is evidence that in obese and lean subjects some 5-HT drugs can readily reduce the intake of high fat foods. Data also suggest that 5-HT activation can lead to a selective avoidance of fat in the diet. These effects of 5-HT on the intake of dietary fat may involve a pre-absorptive mechanism and there is evidence that 5-HT is linked to cholecystokinin and enterostatin. These proposals have theoretical and practical implications and suggest possible strategies to intensify or advance fat-induced satiety signals.     

The Histaminergic Tuberomamillary Nucleus Is Involved in Appetite for Sex,Water and Amphetamine

The histaminergic system is one component of the ascending arousal system which is involved in wakefulness, neuroendocrine control, cognition, psychiatric disorders and motivation. During the appetitive phase of motivated behaviors the arousal state rises to an optimal level, thus giving proper intensity to the behavior. Previous studies have demonstrated that the histaminergic neurons show an earlier activation during the appetitive phase of feeding, compared to other ascending arousal system nuclei, paralleled with a high increase in arousal state. Lesions restricted to the histaminergic neurons in rats reduced their motivation to get food even after 24h of food deprivation, compared with intact or sham lesioned rats. Taken together, these findings indicate that the histaminergic system is important for appetitive behavior related to feeding. However, its role in other goal-directed behaviors remains unexplored. In the present work, male rats rendered motivated to obtain water, sex, or amphetamine showed an increase in Fos-ir of histaminergic neurons in appetitive behaviors directed to get those reinforcers. However, during appetitive tests to obtain sex, or drug in amphetamine-conditioned rats, Fos expression increased in most other ascending arousal system nuclei, including the orexin neurons in the lateral hypothalamus, dorsal raphe, locus coeruleus and laterodorsal tegmental neurons, but not in the ventral tegmental area, which showed no Fos-ir increase in any of the 3 conditions. Importantly, all these appetitive behaviors were drastically reduced after histaminergic cell-specific lesion, suggesting a critical contribution of histamine on the intensity component of several appetitive behaviors.     

Neuro-evolutionary patterning of sociality

Evolutionary shifts in species-typical group size ('sociality') probably reflect natural selection on motivational processes such as social arousal, approach-avoidance, reward, stress/anxiety and dominance. Using four songbird species that differ selectively in sociality (one territorial, one modestly gregarious, and two highly gregarious species), we here examined immediate early gene (IEG) responses of relevant brain regions following exposure to a same-sex conspecific. The paradigm limited behavioural performance, thus species differences should reflect divergence in motivational and/or perceptual processes. Within the extended medial amygdala (which is involved in appetitive approach, social arousal and avoidance), we observed species differences in IEG response that are negatively graded in relation to sociality. In addition, brain areas that are involved in social stress and dominance-related behaviour (ventrolateral septum, anterior hypothalamus and lateral subdivision of the ventromedial hypothalamus) exhibited IEG responses that dichotomously distinguish the territorial species from the three gregarious species. The IEG responses of areas involved in reward (nucleus accumbens and ventral pallidum) and general stress processes (e.g. paraventricular hypothalamus, lateral bed nucleus of the stria terminalis and most areas of the lateral septum) do not correlate with sociality, indicating that social evolution has been accompanied by selection on a relatively discrete suite of motivational systems.     

Role of serotonin receptors in the amygdaloid complex and central gray substance in conditioned passive avoidance reaction in rats

The functional role of 5-HT1 receptors in the memory trace retrieval was investigated in amygdala (AM), central gray substance of midbrain (CGS) and frontal cortex. There is used the passive avoidance response in the rat. The decrease of 5-HT1 binding sites in AM and CGS was revealed for the rats with retention of the passive avoidance response. The binding of 3H-5-HT in AM was found two sets of binding sites. It was concluded, that 5-HT1 receptors of AM and CGS are involved in learning processes either in the moment of the memory trace retrieval or immediately after it.     

Get in My Belly: Food Preferences Trigger Approach and Avoidant Postural Asymmetries

Appetitive motivational states are fundamental neural and behavioral mechanisms underlying healthy and abnormal eating behavior, though their dynamic influence on food-related behavior is unknown. The present study examined whether personal food-related preferences would activate approach and avoidance systems, modulating spontaneous postural sway toward and away from food items. Participants stood on a balance board that collected real-time data regarding postural sway along two axes (x, y) while they viewed a series of images depicting food items varying in nutritional value and individual preferences. Overall, participants showed reliable postural sway toward highly preferred and away from highly non-preferred items. This effect became more pronounced over time; sway along the mediolateral axis showed no reliable variation by preference. Results carry implications for two-factor (homeostatic versus hedonic) neurobehavioral theories of hunger and appetitive motivation, and carry applied clinical implications for the measurement and management of abnormal eating behavior.     

5-HT and 5-HT-SO4, but not tryptophan or 5-HIAA levels in single feeding neurons track animal hunger state

Serotonin (5-HT) is an intrinsic modulator of neural network excitation states in gastropod molluscs. 5-HT and related indole metabolites were measured in single, well-characterized serotonergic neurons of the feeding motor network of the predatory sea-slug Pleurobranchaea californica . Indole amounts were compared between paired hungry and satiated animals. Levels of 5-HT and its metabolite 5-HT-SO₄ in the metacerebral giant neurons were observed in amounts approximately four-fold and two-fold, respectively, below unfed partners 24 h after a satiating meal. Intracellular levels of 5-hydroxyindole acetic acid and of free tryptophan did not differ significantly with hunger state. These data demonstrate that neurotransmitter levels and their metabolites can vary in goal-directed neural networks in a manner that follows internal state.     

A Homeostatic Sleep-Stabilizing Pathway in Drosophila Composed of the Sex Peptide Receptor and Its Ligand,the Myoinhibitory Peptide

Sleep, a reversible quiescent state found in both invertebrate and vertebrate animals, disconnects animals from their environment and is highly regulated for coordination with wakeful activities, such as reproduction. The fruit fly, Drosophila melanogaster, has proven to be a valuable model for studying the regulation of sleep by circadian clock and homeostatic mechanisms. Here, we demonstrate that the sex peptide receptor (SPR) of Drosophila, known for its role in female reproduction, is also important in stabilizing sleep in both males and females. Mutants lacking either the SPR or its central ligand, myoinhibitory peptide (MIP), fall asleep normally, but have difficulty in maintaining a sleep-like state. Our analyses have mapped the SPR sleep function to pigment dispersing factor (pdf) neurons, an arousal center in the insect brain. MIP downregulates intracellular cAMP levels in pdf neurons through the SPR. MIP is released centrally before and during night-time sleep, when the sleep drive is elevated. Sleep deprivation during the night facilitates MIP secretion from specific brain neurons innervating pdf neurons. Moreover, flies lacking either SPR or MIP cannot recover sleep after the night-time sleep deprivation. These results delineate a central neuropeptide circuit that stabilizes the sleep state by feeding a slow-acting inhibitory input into the arousal system and plays an important role in sleep homeostasis.     

D-fenfluramine,but not d-norfenfluramine,uses calcium to increase extracellular serotonin

Microdialysis in the hippocampus of freely moving rats was used to assess extracellular serotonin (5-HT) in response to local infusion of d-fenfluramine and its metabolite d-norfenfluramine with and without local calcium depletion. Verapamil (1 mM) in calcium-free Ringer infused via the microdialysis probe increased extracellular 5-HT and prevented the full increase in extracellular 5-HT normally caused by 1 mM d-fenfluramine. The results suggest d-fenfluramine might act in part as a calcium channel agonist favoring a calcium influx that in turn would trigger the exocytotic process in 5-HT terminals, d-norfenfluramine, on the other hand, was capable of releasing 5-HT, in vivo, in spite of depleted Ca levels.     

A neural theory of circadian rhythms: split rhythms, after-effects and motivational interactions

A neural theory of the circadian pacemaker within the hypothalamic suprachiasmatic nuclei (SCN) is used to explain parametric data about mammalian operant behavior. The intensity, duration, and patterning of ultradian activity-rest cycles and the duration of circadian periods due to parametric (LL) and nonparametric (LD) lighting regimes are simulated. Paradoxical data about split rhythms and after-effects are explained using homeostatic and nonhomeostatic neural mechanisms that modulate pacemaker activity. These modulatory mechanisms enable the pacemaker to adjust to pervasive changes in its lighting regime, as during the passage of seasons, and to ultradian changes in internal metabolic conditions. The model circadian mechanisms are homologous to mechanisms that model hypothalamically mediated appetitive behaviors, such as eating. The theory thus suggests that both circadian and appetitive hypothalamic circuits are constructed from similar neural components. Mechanisms of transmitter habituation, opponent feedback interactions between on-cells and off-cells, homeostatic negative feedback, and conditioning are used in both the circadian and the appetitive circuits. Output from the SCN circadian pacemaker is assumed to modulate the sensitivity of the appetitive circuits to external and internal signals by controlling their level of arousal. Both underarousal and overarousal can cause abnormal behavioral syndromes whose properties have been found in clinical data. A model pacemaker can also be realized as an intracellular system.     

Hypocretins: The Timing of Sleep and Waking

The appropriate time and place for sleep and waking are important factors for survival. Sleep and waking, rest and activity, flight and fight, feeding, and reproduction are all organized in relation to the day and night. A biological clock, the suprachiasmatic nucleus (SCN), synchronized by photic influences and other environmental cues, provides an endogenous timing signal that entrains circadian body rhythms and is complemented by a homeostatic sleep pressure factor. Cholinergic, catecholaminergic, serotonergic, and histaminergic nuclei control wakefulness and mutually interact with the SCN as well as sleep‐ and wake‐promoting neurons in the hypothalamus to form a bistable switch that controlls the timing of behavioral state transitions. Hypocretin neurons integrate circadian‐photic and nutritional‐metabolic influences and act as a conductor in the aminergic orchestra. Their loss causes narcolepsy, a disease conferring the inability to separate sleep and waking. Their role in appetitive behavior, stress, and memory functions is important to our understanding of addiction and compulsion.     

Single amino acids in sucrose rewards modulate feeding and associative learning in the honeybee

Obtaining the correct balance of nutrients requires that the brain integrates information about the body’s nutritional state with sensory information from food to guide feeding behaviour. Learning is a mechanism that allows animals to identify cues associated with nutrients so that they can be located quickly when required. Feedback about nutritional state is essential for nutrient balancing and could influence learning. How specific this feedback is to individual nutrients has not often been examined. Here, we tested how the honeybee’s nutritional state influenced the likelihood it would feed on and learn sucrose solutions containing single amino acids. Nutritional state was manipulated by pre-feeding bees with either 1 M sucrose or 1 M sucrose containing 100 mM of isoleucine, proline, phenylalanine, or methionine 24 h prior to olfactory conditioning of the proboscis extension response. We found that bees pre-fed sucrose solution consumed less of solutions containing amino acids and were also less likely to learn to associate amino acid solutions with odours. Unexpectedly, bees pre-fed solutions containing an amino acid were also less likely to learn to associate odours with sucrose the next day. Furthermore, they consumed more of and were more likely to learn when rewarded with an amino acid solution if they were pre-fed isoleucine and proline. Our data indicate that single amino acids at relatively high concentrations inhibit feeding on sucrose solutions containing them, and they can act as appetitive reinforcers during learning. Our data also suggest that select amino acids interact with mechanisms that signal nutritional sufficiency to reduce hunger. Based on these experiments, we predict that nutrient balancing for essential amino acids during learning requires integration of information about several amino acids experienced simultaneously.     

Evolution and function in serotonergic systems

Serotonergic systems of invertebrate and vertebrate centralnervous systems (CNS) are functionally similar in multiple characters.Serotonin (5-HT) neurons dispersed throughout the CNS of lophotrochozoaninvertebrates (molluscs and leeches) are analogous to vertebrate5-HT neurons concentrated in the raphe nuclei of mid- and hindbrain:they innervate specific central pattern generators and othercircuits of the CNS, receive feedback from them, and supportgeneral behavioral arousal. In both groups 5-HT regulates excitatorygain of CNS circuitry and uses similarly diverse 5-HT receptors.Marked contrast, however, exists for roles of 5-HT in regulationof appetite. Where invertebrate 5-HT neurons promote an appetitivestate, this role is supplanted in the vertebrates by a peptidergicnetwork centered around orexins/hypocretins, to which the roleof 5-HT in arousal is subordinate. In the vertebrates, 5-HThas appetite-suppressant properties. This is paralleled by differingcomplexities of mechanisms that bring about satiety. Lophotrozoansappear to rely on simple stretching of the gut, with no obviousfeedback from true nutrient stores. In contrast, vertebrateappetite is regulated by hypothalamic sensitivity to hormonalsignals reporting separately on the status of fat cells anddigestive activity, and to blood glucose, in addition to gutstretch. The simple satiety mechanism of a mollusc can be usedin value-based foraging decisions that integrate hunger state,taste, and experience (Gillette and others 2000). For vertebrates,where appetite and arousal are regulated by signals from long-livednutrient stores, decisions can be based on resource need goingfar beyond simple gut content, enabling value estimation andrisk assessment in the longer-term. Thus, connection of nutrientstorage depots to CNS circuitry mediating appetite may supplycritical substrate for evolving complexity in brain and behavior.This hypothesis may be tested in expanded comparative studiesof 5-HT and peptidergic functions in appetite and arousal.     

Antipredator responses of aphids to parasitoids change as a function of aphid physiological state

Under predation risk, prey may prioritize antipredator behaviours and sacrifice feeding. However, energetically constrained animals may choose to sacrifice or change antipredator responses and accept relatively greater risk in order to secure food. In this last case, the antipredator tactics chosen must balance safety and feeding in such a way that costs are minimized and benefits maximized. We studied the antipredator behaviour of pea aphid, Acyrthosiphon pisum (Harris) (Hemiptera: Aphididae) subjected to different periods of food deprivation, against the parasitoid Aphidius ervi (Hymenoptera: Braconidae). As the energetic internal stress of aphids increased, the predominant antipredator response changed from walking away and dropping to kicking behaviour, and parasitization avoidance decreased. Parasitoids did not show preference between food-deprived and nonfood-deprived aphids. Dropping and walking away reduced parasitization from 50 to 33%. These results support the hypothesis that the antipredator behaviour of an aphid changes as a function of internal stress. By performing less costly behaviour such as kicking under energetically constrained conditions, aphids seem to minimize their probability of energy shortfall. Given that aphid antipredator behaviour is a function of nutritional state, its occurrence under natural conditions may match host quality spatial distribution. Copyright 2002 The Association for the Study of Animal Behaviour. Published by Elsevier Science Ltd. All rights reserved.     

Dissecting the serotonergic food signal stimulating sensory-mediated aversive behavior in C. elegans

Nutritional state often modulates olfaction and in Caenorhabditis elegans food stimulates aversive responses mediated by the nociceptive ASH sensory neurons. In the present study, we have characterized the role of key serotonergic neurons that differentially modulate aversive behavior in response to changing nutritional status. The serotonergic NSM and ADF neurons play antagonistic roles in food stimulation. NSM 5-HT activates SER-5 on the ASHs and SER-1 on the RIA interneurons and stimulates aversive responses, suggesting that food-dependent serotonergic stimulation involves local changes in 5-HT levels mediated by extrasynaptic 5-HT receptors. In contrast, ADF 5-HT activates SER-1 on the octopaminergic RIC interneurons to inhibit food-stimulation, suggesting neuron-specific stimulatory and inhibitory roles for SER-1 signaling. Both the NSMs and ADFs express INS-1, an insulin-like peptide, that appears to cell autonomously inhibit serotonergic signaling. Food also modulates directional decisions after reversal is complete, through the same serotonergic neurons and receptors involved in the initiation of reversal, and the decision to continue forward or change direction after reversal is dictated entirely by nutritional state. These results highlight the complexity of the "food signal" and serotonergic signaling in the modulation of sensory-mediated aversive behaviors.     

Angiotensin II in dorsomedial hypothalamus modulates cardiovascular arousal caused by stress but not feeding in rabbits

The dorsomedial hypothalamus (DMH) is critically implicated in the cardiovascular response to emotional stress. This study aimed to determine whether the DMH is also important in cardiovascular arousal associated with appetitive feeding behavior and, if so, whether locally released angiotensin II and glutamate are important in this arousal. Emotional (air-jet) stress and feeding elicited similar tachycardic (+51 and +45 beats/min, respectively) and pressor (+16 and +9 mmHg, respectively) responses in conscious rabbits. Bilateral microinjection of GABA(A) agonist muscimol (500 pmol) into the DMH, but not nearby hypothalamic regions, attenuated pressor and tachycardic responses to air-jet by 56-63% and evoked anorexia. Conversely, stimulation of the DMH with the glutamate analog kainic acid (250 pmol) elicited hypertension (+25 mmHg) and tachycardia (+114 beats/min) and activated feeding behavior. Local microinjection of a glutamate receptor antagonist, kynurenic acid (10 nmol), decreased pressor responses to stress and eating by 46 and 72%, respectively, without affecting feeding behavior. Bilateral microinjection of a selective AT(1)-receptor antagonist, candesartan (500 pmol), into the DMH, but not nearby sites, attenuated pressor and tachycardic stress responses by 31 and 33%, respectively. Candesartan did not alter feeding behavior or circulatory response to feeding. These results indicate that, in addition to its role in mediating stress responses, the DMH may be important in regulating cardiovascular arousal associated with feeding. Local glutamatergic inputs appear to regulate cardiovascular response to both stress and feeding. Conversely, angiotensin II, acting via AT1 receptors, may selectively modulate, in the DMH, cardiovascular response to stress, but not feeding.     

Evaluation of a Cys23Ser mutation within the human 5-HT2C receptor gene: No evidence for an association of the mutant allele with obesity or underweight in children,adolescents and young adults

Serotonin is a neurotransmitter involved in a large number of psychophysiological processes including the regulation of mood, arousal, aggression, sleep, learning, nociceptions, nerve growth and importantly, appetitive functions. Alterations of 5-HT receptor activity have been shown to occur in many psychiatric diseases including depression, anxiety, eating disorders, schizophrenia etc. Hence, genetic variation in genes coding for serotonin receptor proteins might well be involved in the genetic predisposition to these diseases and therefore are of great pharmacogenetic relevance. Knockout mice deficient of a functional 5-HT2C receptor have implicated a potential role of this receptor subtype in the serotonergic control of appetite. A Cys23Ser mutation in the human 5-HT2C receptor gene discovered recently prompted us to investigate this mutation with regard to the development of human obesity. We have evaluated this mutation in 241 obese children and adolescents (mean BMI ≥ 97th percentile), 80 normal weight children (BMI 5th – 85th percentile) and 92 underweight probands (BMI ≤ 15th percentile) for a possible association with obesity. The frequencies of the mutant allele in all three weight groups (obese subjects: 0.1597; normal weight: 0.168; underweight: 0.1575) were very similar. Association as well as linkage studies were negative. Therefore it is unlikely that this receptor mutation plays a direct role in the development of human obesity.     

Effect of Flumethrin on Survival and Olfactory Learning in Honeybees

Flumethrin has been widely used as an acaricide for the control of Varroa mites in commercial honeybee keeping throughout the world for many years. Here we test the mortality of the Asian honeybee Apis cerana cerana after treatment with flumethrin. We also ask (1) how bees react to the odor of flumethrin, (2) whether its odor induces an innate avoidance response, (3) whether its taste transmits an aversive reinforcing component in olfactory learning, and (4) whether its odor or taste can be associated with reward in classical conditioning. Our results show that flumethrin has a negative effect on Apis ceranàs lifespan, induces an innate avoidance response, acts as a punishing reinforcer in olfactory learning, and interferes with the association of an appetitive conditioned stimulus. Furthermore flumethrin uptake within the colony reduces olfactory learning over an extended period of time.