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Rang social, système dopaminergique et réponse au stress
Abstract
L'organisation hiérarchique est la marque de nombreux vertébrés. Des associations entre rang social et état de santé sont signalées chez de nombreuses espèces incluant l’humain. Cependant, les mécanismes impliqués sont mal compris. La réponse au stress, spécifique au rang social chez de nombreux animaux, intervient dans de nombreuses pathologies psychiatriques. Ceci suggère un rôle de la réponse au stress dans le processus liant statut social et comportement. Mon travail de thèse vise à mieux comprendre les associations qui existent entre le rang social et le comportement individuel chez la souris. Mon travail vise à clarifier la direction de cette association en observant les conséquences du rang social sur le comportement et la vulnérabilité aux maladies psychiatriques, et réciproquement, en identifiant des marqueurs individuels précoces pouvant contribuer à façonner le destin social. Au niveau physiologique, je me concentre sur la réponse au stress et ses conséquences sur le système dopaminergique (DA), en tant que médiateur potentiel des phénotypes sociaux. Pour répondre à ces questions, j'ai évalué le rang social de mâles adultes C57BL/6 via des tests compétitifs. J'ai ensuite testé ces animaux pour l'anxiété, la sociabilité et les compétences cognitives, avant et après établissement hiérarchique. Nous avons enregistré l'activité électrophysiologique de cellules DA dans la région tégmentale ventrale. J'ai quantifié la libération de DA dans la voie mésocorticolimbique et testé les souris pour la dépression et la dépendance. Enfin, j’ai évalué les conséquences d’une inactivation du récepteur des glucocorticoïdes dans les cellules DAceptives pour la dominance sociale.
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The role of the amygdala in dyadic social interactions of adult rhesus monkeys (Macaca mulatta) was assessed after bilateral ibotenic acid lesions. Social, nonsocial, and spatial behaviors of amygdalectomized and control monkeys were assessed in 3 dyadic experiments: constrained, unconstrained, and round robin. Lesions produced extensive bilateral damage to the amygdala. Across all experiments, the amygdalectomized monkeys demonstrated increased social affiliation, decreased anxiety, and increased confidence compared with control monkeys, particularly during early encounters. Normal subjects also demonstrated increased social affiliation toward the amygdalectomized subjects. These results indicate that amygdala lesions in adult monkeys lead to a decrease in the species-normal reluctance to immediately engage a novel conspecific in social behavior. The altered behavior of the amygdalectomized monkeys may have induced the increased social interactions from their normal companions. This is contrary to the idea that amygdalectomy produces a decrease in social interaction and increased aggression from conspecifics.
The authors investigated the influence of associative pairing of contextual stimuli with amphetamine administration on the expression of psychomotor sensitization. Animals received d-amphetamine or saline in group-specific environments. Amphetamine produced robust behavioral sensitization in all environments, but when an amphetamine challenge was given in a test environment that was novel for some groups but not others, the expression of sensitization was completely context specific. An injection of saline in the amphetamine-paired environment produced a conditional response (CR), but this was quite small compared to the magnitude of the sensitized response, and sensitization remained completely context specific following extinction of the CR. Results are discussed in relation to 3 models of how context may modulate the expression of sensitization: an excitatory conditioning model, an inhibitory conditioning model, and an occasion-setting model.
The glucocorticoid receptor (GR) binds the noncoding RNA Gas5 via its DNA-binding domain (DBD) with functional implications in pro-apoptosis signaling. Here, we report a comprehensive in vitro binding study where we have determined that GR-DBD is a robust structure-specific RNA-binding domain. GR-DBD binds to a diverse range of RNA hairpin motifs, both synthetic and biologically derived, with apparent mid-nanomolar affinity while discriminating against uniform dsRNA. As opposed to dimeric recognition of dsDNA, GR-DBD binds to RNA as a monomer and confers high affinity primarily through electrostatic contacts. GR-DBD adopts a discrete RNA-bound state, as assessed by NMR, distinct from both free and DNA-bound. NMR and alanine mutagenesis suggest a heightened involvement of the C-terminal α-helix of the GR-DBD in RNA-binding. RNA competes for binding with dsDNA and occurs in a similar affinity range as dimer binding to the canonical DNA element. Given the prevalence of RNA hairpins within the transcriptome, our findings strongly suggest that many RNAs have potential to impact GR biology.
Cocaine is known to increase the extracellular levels of dopamine (DA) and serotonin (5-HT) by inhibiting the neuronal reuptake of these monoamines. However, individuals with reduced monoamine reuptake transporter expression do not display a reduction in cocaine intake, suggesting that a mechanism other than inhibition of monoamine reuptake contributes to the rewarding and addictive effects of the psychostimulant. Here we report that cocaine depletes the dopaminergic and serotonergic storage vesicles of the rat nucleus accumbens. This cocaine-induced vesicle depletion gave rise to acute increases in the extracellular levels of DA and 5-HT, which in turn correlated with monoamine-type-specific changes in behavior. Both the neurochemical and behavioral responses to cocaine varied among individual animals, which was not due to individual differences in the reuptake of DA and 5-HT, but rather to individual differences in their vesicular release. Furthermore, we found that reserpine-induced depletion of storage vesicles reduced both short and long access cocaine self-administration, and the degree of reduction was linked to the vesicular storage capacity of the animals. In conclusion, we demonstrate a novel mechanism by which cocaine increases the extracellular concentrations of accumbal DA and 5-HT, namely via release from storage vesicles. Furthermore, individual differences in cocaine-induced vesicular monoamine release shape individual differences in not only the acute behavioral and neurochemical effects of the stimulant, but also in its intake. Thus, intracellular storage vesicles represent an attractive novel drug target to combat psychostimulant addiction.
Social behavior in mammals is often studied in pairs under artificial conditions, yet groups may rely on more complicated social structures. Here, we use a novel system for tracking multiple animals in a rich environment to characterize the nature of group behavior and interactions, and show strongly correlated group behavior in mice. We have found that the minimal models that rely only on individual traits and pairwise correlations between animals are not enough to capture group behavior, but that models that include third-order interactions give a very accurate description of the group. These models allow us to infer social interaction maps for individual groups. Using this approach, we show that environmental complexity during adolescence affects the collective group behavior of adult mice, in particular altering the role of high-order structure. Our results provide new experimental and mathematical frameworks for studying group behavior and social interactions.
The forced swim test (FST) for rodents does not model despair or helplessness. It also is not a read-out for depression, anxiety, psychomotor retardation or autism, because these are anthropomorphic interpretations of the rodent's acquired immobility. Rather, the transition from swimming to immobility allows to examine the mechanistic underpinning of coping with inescapable stressors. However, in a recent detailed analysis of the FST application over the past 40 years, we noted a dramatic surge in the use of this test to phenotype animals as ‘depressed’. As a follow up to that report, we now present an analysis of the use of the FST over the past three years. This literature analysis shows that the popularity of the FST is still increasing and that the majority of researchers qualifies the rodent's floating response as depressive-like behavior. However, over the past few years we also note a trend to interpret immobility rather as the expression of a coping strategy. In view of this result, we have sent a poll to the relevant authors to learn how consistent they are in naming FST behavior. Remarkably, we find a dramatic inverse correlation between their first qualification of acquired immobility as depressive-like behavior towards their current interpretation as coping strategy. In this contribution we have embedded our literature analysis and poll results in an update on the management of coping with inescapable stressors by processing in prefrontal cortical circuitry and glucocorticoid feedback.
Reproductive synchrony is a widespread phenomenon that is predicted to be adaptive for prey with specialist predators but not for those with generalist ones. I tested this prediction in three polar seabird species characterized by different levels of predator specialization. In the Antarctic petrel, for which the only predator was highly specialized, hatching dates were highly synchronous and chicks that hatched close to the mean hatching date had a higher survival. In black‐legged kittiwakes and Brünnich's guillemots, whose predators were generalists, breeding was less synchronous and there was no fitness advantage in hatching close to the mean. This study emphasizes the potential importance of the relative timing of reproduction for individual fitness and supports the hypothesis that the adaptive value of breeding synchrony depends on the predator functional response.
Low social status is an important predictor of disease susceptibility and mortality risk in humans and other social mammals. These effects are thought to stem in part from dysregulation of the glucocorticoid (GC)-mediated stress response. However, the molecular mechanisms that connect low social status and GC dysregulation to downstream health outcomes remain elusive. Here, we used an in vitro GC challenge to investigate the consequences of experimentally manipulated social status (i.e., dominance rank) for immune cell gene regulation in female rhesus macaques, using paired control and GC-treated peripheral blood mononuclear cell samples. We show that social status not only influences immune cell gene expression but also chromatin accessibility at hundreds of regions in the genome. Social status effects on gene expression were less pronounced following GC treatment than under control conditions. In contrast, social status effects on chromatin accessibility were stable across conditions, resulting in an attenuated relationship between social status, chromatin accessibility, and gene expression after GC exposure. Regions that were more accessible in high-status animals and regions that become more accessible following GC treatment were enriched for a highly concordant set of transcription factor binding motifs, including motifs for the GC receptor cofactor AP-1. Together, our findings support the hypothesis that social status alters the dynamics of GC-mediated gene regulation and identify chromatin accessibility as a mechanism involved in social stress-driven GC resistance. More broadly, they emphasize the context-dependent nature of social status effects on gene regulation and implicate epigenetic remodeling of chromatin accessibility as a contributing factor.
The nucleus accumbens (NAc) contains multiple subpopulations of medium spiny neurons (MSNs). One subpopulation expresses D1-type dopamine receptors, another expresses D2-type receptors, and a third expresses both. The relative roles in NAc of D1 neurons versus D2 neurons in appetitive motivation were assessed here. Specifically, we asked whether D1-Cre mice would instrumentally seek optogenetic self-stimulation specifically targeted at D1 MSNs in NAc, and similarly if D2-Cre mice would self-stimulate D2 neurons in NAc. Mice were implanted with Cre-targeted channelrhodopsin (ChR2) virus and optic fibers in NAc. Subsequently, mice could earn brief NAc laser illuminations by actively touching a metal spout in one task, or by going to a particular location in a separate task. Results indicated that D1 neuronal excitation in NAc supported intense self-stimulation in both tasks. D1-Cre mice earned hundreds to thousands of spout-touches per half-hour session, and also sought out locations that delivered NAc laser to excite D1 MSNs. By comparison, D2 ChR2 mice showed lower but still positive levels of self-stimulation in the spout-touch task, earning dozens to hundreds of NAc laser illuminations. However, in the location task, D2 mice failed to show positive self-stimulation. If anything, a few D2 individuals gradually avoided the laser location. Brain-wide measures indicated that D1 and D2 stimulations in NAc recruited heavily overlapping patterns of Fos activation in distant limbic structures. These results confirm that excitation of D1 MSNs in NAc supports strong incentive motivation to self-stimulate. They also suggest that excitation of D2 neurons in NAc supports self-stimulation under some conditions, but fails under others and possibly may even shift to negative avoidance.
Midbrain dopamine (DA) neurons play a crucial role in the formation of conditioned associations between environmental cues and appetitive events. Activation of N-methyl-D-aspartate (NMDA) receptors is a key mechanism responsible for the generation of conditioned responses of DA neurons to reward cues. Here, we tested the effects of the cell type-specific inactivation of NMDA receptors in DA neurons in adult mice on stimulus-reward learning. Animals were trained in a Pavlovian learning paradigm in which they had to learn the predictive value of two conditioned stimuli, one of which (CS+) was paired with the delivery of a water reward. Over the course of conditioning, mutant mice learned that the CS+ predicted reward availability, and they approached the reward receptacle more frequently during CS+ trials than CS- trials. However, conditioned responses to the CS+ were weaker in the mutant mice, possibly indicating that they did not attribute incentive salience to the CS+. To further assess whether the attribution of incentive salience was impaired by the mutation, animals were tested in a conditioned reinforcement test. The test revealed that mutant mice made fewer instrumental responses paired with CS+ presentation, confirming that the CS+ had a weaker incentive value. Taken together, these results indicate that reward prediction learning does occur in the absence of NMDA receptors in DA neurons, but the ability of reward-paired cues to invigorate and reinforce behavior is lost.
Dopamine plays a key role in the cellular and behavioral responses to drugs of abuse, but the implication of metabotropic regulatory input to dopaminergic neurons on acute drug effects and subsequent drug-related behavior remains unclear. Here, we used chemogenetics [Designer Receptors Exclusively Activated by Designer Drugs (DREADDs)] to modulate dopamine signaling and activity before cocaine administration in mice. We show that chemogenetic inhibition of dopaminergic ventral tegmental area (VTA) neurons differentially affects locomotor and reward-related behavioral responses to cocaine. Stimulation of Gi-coupled DREADD (hM4Di) expressed in dopaminergic VTA neurons persistently reduced the locomotor response to repeated cocaine injections. An attenuated locomotor response was seen even when a dual-viral vector approach was used to restrict hM4Di expression to dopaminergic VTA neurons projecting to the nucleus accumbens. Surprisingly, despite the attenuated locomotor response, hM4Di-mediated inhibition of dopaminergic VTA neurons did not prevent cocaine sensitization, and the inhibitory effect of hM4Di-mediated inhibition was eliminated after withdrawal. In the conditioned place-preference paradigm, hM4Di-mediated inhibition did not affect cocaine-induced place preference; however, the extinction period was extended. Also, hM4Di-mediated inhibition had no effect on preference for a sugar-based reward over water but impaired motivation to work for the same reward in a touchscreen-based motivational assay. In addition, to support that VTA dopaminergic neurons operate as regulators of reward motivation toward both sugar and cocaine, our data suggest that repeated cocaine exposure leads to adaptations in the VTA that surmount the ability of Gi-signaling to suppress and regulate VTA dopaminergic neuronal activity.
Studies of intravenous self-administration and psychomotor effects of drugs have recently suggested that stress-induced corticosterone secretion may be an important factor determining vulnerability to drugs of abuse. In this report, we studied if basal physiological corticosterone secretion modulates sensitivity to cocaine and morphine, and if changes in the reactivity of mesolimbic dopaminergic (DA) neurons, one of the principal substrates of drug-reinforcing effects, are involved. For this purpose we determined the psychomotor effects of these drugs in animals in which corticosterone secretion was suppressed by adrenalectomy and in adrenalectomized animals submitted to different corticosterone replacement therapies designed to mimic (1) only the diurnal levels of the hormone, obtained by the subcutaneous implantation of 50 mg corticosterone pellets; (2) only the nocturnal levels, obtained by adding corticosterone (50 micrograms/ml) to the drinking solution during the dark period; and (3) the entire circadian fluctuation, obtained by combining the two previous treatments. Locomotor response to cocaine and morphine was studied after both systemic and central injections, into the nucleus accumbens for cocaine and into the ventral tegmental area for morphine. These sites were chosen because stimulant effects of cocaine and morphine injected in these structures are dopamine dependent. Our results show that suppression of corticosterone by adrenalectomy reduced the locomotor response to cocaine and morphine, injected both systemically and centrally. The reinstatement of diurnal levels of corticosterone totally reversed adrenalectomy's effects on the behavioral response to cocaine, whereas the reestablishment of the entire corticosterone circadian fluctuation (diurnal plus nocturnal levels) was necessary to reverse the response to morphine.(ABSTRACT TRUNCATED AT 250 WORDS)
GABAergic neurons in the ventral tegmental area (VTA) play a primary role in local inhibition of mesocorticolimbic dopamine (DA) neurons but are not physiologically or anatomically well characterized. We used in vivo extracellular and intracellular recordings in the rat VTA to identify a homogeneous population of neurons that were distinguished from DA neurons by their rapid-firing, nonbursting activity (19.1 +/- 1.4 Hz), short-duration action potentials (310 +/- 10 microseconds), EPSP-dependent spontaneous spikes, and lack of spike accommodation to depolarizing current pulses. These non-DA neurons were activated both antidromically and orthodromically by stimulation of the internal capsule (IC; conduction velocity, 2.4 +/- 0.2 m/sec; refractory period, 0.6 +/- 0.1 msec) and were inhibited by stimulation of the nucleus accumbens septi (NAcc). Their firing rate was moderately reduced, and their IC-driven activity was suppressed by microelectrophoretic application or systemic administration of NMDA receptor antagonists. VTA non-DA neurons were recorded intracellularly and showed relatively depolarized resting membrane potentials (-61.9 +/- 1.8 mV) and small action potentials (68.3 +/- 2.1 mV). They were injected with neurobiotin and shown by light microscopic immunocytochemistry to be multipolar cells and by electron microscopy to contain GABA but not the catecholamine-synthesizing enzyme tyrosine hydroxylase (TH). Neurobiotin-filled dendrites containing GABA received asymmetric excitatory-type synapses from unlabeled terminals and symmetric synapses from terminals that also contained GABA. These findings indicate that VTA non-DA neurons are GABAergic, project to the cortex, and are controlled, in part, by a physiologically relevant NMDA receptor-mediated input from cortical structures and by GABAergic inhibition.
Although previous research has emphasized the beneficial effects of dopamine (DA) on functions of the prefrontal cortex (PFC), recent studies of animals exposed to mild stress indicate that excessive DA receptor stimulation may be detrimental to the spatial working memory functions of the PFC (Arnsten and Goldman-Rakic, 1990; Murphy et al., 1994, 1996a,b, 1997). In particular, these studies have suggested that supranormal stimulation of D 1 receptors may contribute to the detrimental actions of DA in the PFC (Murphy et al., 1994, 1996a). The current study directly tested this hypothesis by examining the effects of infusing a full D 1 receptor agonist, SKF 81297, into the PFC of rats performing a spatial working memory task, delayed alternation. SKF 81297 produced a dose-related impairment in delayed-alternation performance. The impairment was reversed by pretreatment with a D 1 receptor antagonist, SCH 23390, consistent with drug actions at D 1 receptors. SCH 23390 by itself had no effect on performance, although slightly higher doses impaired performance (Murphy et al., 1994, 1996a). There was a significant relationship between infusion location and drug efficacy; animals with cannulae anterior to the PFC were not impaired by SKF 81297 infusions. Taken together, these results demonstrate that supranormal D 1 receptor stimulation in the PFC is sufficient to impair PFC working memory function. These cognitive data are consistent with recent electrophysiological studies of D 1 receptor mechanisms affecting the PFC (Williams and Goldman-Rakic, 1995; Yang and Seamans, 1996). Increased D 1 receptor stimulation during stress may serve to take the PFC “off-line” to allow posterior cortical and subcortical structures to regulate behavior, but may contribute to the vulnerability of the PFC in many neuropsychiatric disorders.
Two different 19-mer antisense oligodeoxynucleotides complementary to the initial coding regions of dopamine D 2 or D 3 receptor mRNA were infused unilaterally into the substantia nigra of rats for 3–6 d to suppress synthesis of D 2 and/or D 3 receptors on substantia nigra dopaminergic neurons, thereby producing specific reductions of D 2 and/or D 3 receptors. Autoradiographic receptor binding revealed that D 2 and D 3 antisense oligodeoxynucleotides specifically and significantly reduced D 2 or D 3 binding in the ipsilateral substantia nigra, respectively, without affecting dopamine receptor binding in the neostriatum. Either D 2 or D 3 antisense oligodeoxynucleotides greatly attenuated the ability of apomorphine to inhibit dopaminergic neurons in vivo , an effect that was potentiated by simultaneous administration of D 2 and D 3 antisenses. Despite these effects, neither the rate nor the pattern of spontaneous activity of antisense-treated nigrostriatal neurons differed from those in the control groups. The proportion of antidromic responses consisting of full spikes from antisense-treated rats was significantly greater, and the mean antidromic threshold was significantly lower than in controls, indicating that autoreceptor knockdown increased both somatodendritic and terminal excitability. These data demonstrate that selective reduction of specific dopamine receptor subtypes by antisense infusion can be effected in vivo , and that nigrostriatal neurons express both D 2 and D 3 autoreceptors at their somatodendritic and axon terminal regions. Although the somatodendritic and terminal autoreceptors modulate dendritic and terminal excitability, respectively, the interaction of endogenously released dopamine with somatodendritic autoreceptors does not appear to exert a significant effect on spontaneous activity in anesthetized rats.
The functional neuroanatomy of unipolar major depression was investigated using positron emission tomography to measure differences in regional cerebral blood flow (BF). A relatively homogeneous subject group was obtained using criteria for familial pure depressive disease (FPDD), which are based upon family history as well as upon symptoms and course. Because of the absence of certain knowledge about the pathophysiology of mood disorders and their underlying functional neuroanatomy, we used data obtained from the subtraction of composite images from one-half of depressed and control subjects to identify candidate regions of interest. The major cortical region defined in this manner was statistically tested on a second set of subjects. Using this strategy, we found increased BF in an area that extended from the left ventrolateral prefrontal cortex onto the medial prefrontal cortical surface. Based upon the connectivity between these portions of the prefrontal cortex and the amygdala and evidence that the amygdala is involved in emotional modulation, activity was measured in the left amygdala and found to be significantly increased in the depressed group. A separate group of subjects with FPDD who were currently asymptomatic were also imaged to determine whether these findings represented abnormalities associated with the depressed state, or with a trait difference that might underlie the tendency to become depressed. Only the depressed group had increased activity in the left prefrontal cortex, suggesting that this abnormality represents a state marker of FPDD. Both the depressed and the remitted groups demonstrated increased activity in the left amygdala, though this difference achieved significance only in the depressed group. This suggests that the abnormality involving the left amygdala may represent a trait marker of FPDD, though further assessment in a larger sample size is necessary to establish this. These data along with other evidence suggest that a circuit involving the prefrontal cortex, amygdala, and related parts of the striatum, pallidum, and medial thalamus is involved in the functional neuroanatomy of depression.
Individual neostriatal-matrix spiny neurons were stained intracellularly with biocytin after intracellular recording in vivo, and their axons were traced into the globus pallidus (GP), entopeduncular nucleus (EP), and/or substantia nigra (SN). The locations of the neurons within the matrix compartment of the neostriatum (NS) were established by immunocytochemical counterstaining of sections containing the cell bodies using antibodies for calbindin- D28K. This allowed nearly complete visualization of the axonal projections of single NS neurons. On the basis of their intrastriatal axonal arborizations, matrix spiny neurons could be divided into 2 types. One type, which was the more common, had local axonal arborizations restricted to the region of the dendritic field, often with axon collaterals arborizing within the dendritic field of the cells of origin. A second, less common, cell type in the matrix had local axon collaterals distributed widely in the NS. Among matrix neurons with restricted local collateral fields, 3 subtypes could be distinguished on the basis of their efferent axonal projections. Type I cells projected only to the GP. Type IIa cells projected to the GP, EP, and SN pars reticulata. Type IIb cells projected to the GP and SN but not to the EP. The shapes and densities of the GP arborizations varied in the 3 cell types, with the cells projecting only to the GP (type I) projecting more heavily and filling a larger volume there than type II cells. The dendrites and intrastriatal axon collaterals of 3 subtypes were similar in morphology. The class of matrix spiny neurons with intrastriatal axon collaterals distributed widely in the NS were observed to project to the GP. Projections beyond the GP were not identified for this cell type, but could not be ruled out. Somatodendritic morphologies of neurons did not differ according to the projection site. These results demonstrate that NS matrix spiny cells are more heterogeneous in their efferent projection patterns than previously suspected on the basis of retrograde axonal tracing and immunocytochemical studies. As predicted by those previous studies, there is a class of matrix neurons that projects only to the GP. Presumably, these cells contain enkephalin. Cells projecting to the SN and EP, and so presumably containing substance P, give off a small projection to the GP, as well, and differ in their collateralization patterns within the 3 major target nuclei.
The neural control of social behaviors in rodents requires the encoding of pheromonal cues by the vomeronasal system. Here we show that the typical preference of male mice for females is eliminated in mutants lacking oxytocin, a neuropeptide modulating social behaviors in many species. Ablation of the oxytocin receptor in aromatase-expressing neurons of the medial amygdala (MeA) fully recapitulates the elimination of female preference in males. Further, single- unit recording in the MeA uncovered significant changes in the sensory representation of conspecific cues in the absence of oxytocin signaling. Finally, acute manipulation of oxytocin signaling in adults is sufficient to alter social interaction preferences in males as well as responses of MeA neurons to chemosensory cues. These results uncover the critical role of oxytocin signaling in a molecularly defined neuronal population in order to modulate the behavioral and physiological responses of male mice to females on a moment-to-moment basis.
All animals possess a repertoire of innate (or instinctive) behaviours, which can be performed without training. Whether such behaviours are mediated by anatomically distinct and/or genetically specified neural pathways remains unknown. Here we report that neural representations within the mouse hypothalamus, that underlie innate social behaviours, are shaped by social experience. Oestrogen receptor 1-expressing (Esr1+) neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl) control mating and fighting in rodents. We used microendoscopy to image Esr1+neuronal activity in the VMHvl of male mice engaged in these social behaviours. In sexually and socially experienced adult males, divergent and characteristic neural ensembles represented male versus female conspecifics. However, in inexperienced adult males, male and female intruders activated overlapping neuronal populations. Sex-specific neuronal ensembles gradually separated as the mice acquired social and sexual experience. In mice permitted to investigate but not to mount or attack conspecifics, ensemble divergence did not occur. However, 30 minutes of sexual experience with a female was sufficient to promote the separation of male and female ensembles and to induce an attack response 24 h later. These observations uncover an unexpected social experience-dependent component to the formation of hypothalamic neural assemblies controlling innate social behaviours. More generally, they reveal plasticity and dynamic coding in an evolutionarily ancient deep subcortical structure that is traditionally viewed as a ‘hard-wired’ system.
Brain circuits that modulate sociability
Understanding the neural mechanisms that mediate social reward has important societal and clinical implications. Hung et al. found that release of the neuropeptide oxytocin in the ventral tegmental area of the brain increased prosocial behaviors in mice (see the Perspective by Preston). Optogenetic manipulation of oxytocin release influenced sociability in a context-dependent manner. Oxytocin increased activity in dopamine cells that project to the nucleus accumbens, another key node of reward circuitry in the brain.
Science , this issue p. 1406 ; see also p. 1353
Group-housed male mice exhibit aggressive behaviour towards their cage mates and form a social hierarchy. Here, we describe how social hierarchy in standard group-housed conditions affects behaviour and gene expression in male mice. Four male C57BL/6 mice were kept in each cage used in the study, and the social hierarchy was determined from observation of video recordings of aggressive behaviour. After formation of a social hierarchy, the behaviour and hippocampal gene expression were analysed in the mice. Higher anxiety- and depression-like behaviours and elevated gene expression of hypothalamic corticotropin-releasing hormone and hippocampal serotonin receptor subtypes were observed in subordinate mice compared with those of dominant mice. These differences were alleviated by orally administering fluoxetine, which is an antidepressant of the selective serotonin reuptake inhibitor class. We concluded that hierarchy in the home cage affects behaviour and gene expression in male mice, resulting in anxiety- and depression-like behaviours being regulated differently in dominant and subordinate mice.
Dopamine neurons in the ventral tegmental area (VTA) encode reward prediction errors and can drive reinforcement learning through their projections to striatum, but much less is known about their projections to prefrontal cortex (PFC). Here, we studied these projections and observed phasic VTA–PFC fiber photometry signals after the delivery of rewards. Next, we studied how optogenetic stimulation of these projections affects behavior using conditioned place preference and a task in which mice learn associations between cues and food rewards and then use those associations to make choices. Neither phasic nor tonic stimulation of dopaminergic VTA–PFC projections elicited place preference. Furthermore, substituting phasic VTA–PFC stimulation for food rewards was not sufficient to reinforce new cue–reward associations nor maintain previously learned ones. However, the same patterns of stimulation that failed to reinforce place preference or cue–reward associations were able to modify behavior in other ways. First, continuous tonic stimulation maintained previously learned cue–reward associations even after they ceased being valid. Second, delivering phasic stimulation either continuously or after choices not previously associated with reward induced mice to make choices that deviated from previously learned associations. In summary, despite the fact that dopaminergic VTA–PFC projections exhibit phasic increases in activity that are time locked to the delivery of rewards, phasic activation of these projections does not necessarily reinforce specific actions. Rather, dopaminergic VTA–PFC activity can control whether mice maintain or deviate from previously learned cue–reward associations.
Benzodiazepines can ameliorate social disturbances and increase social competition, particularly in high-anxious individuals. However, the neural circuits and mechanisms underlying benzodiazepines’ effects in social competition are not understood. Converging evidence points to the mesolimbic system as a potential site of action for at least some benzodiazepine-mediated effects. Furthermore, mitochondrial function in the nucleus accumbens (NAc) has been causally implicated in the link between anxiety and social competitiveness. Here, we show that diazepam facilitates social dominance, ameliorating both the competitive disadvantage and low NAc mitochondrial function displayed by high-anxious rats, and identify the ventral tegmental area (VTA) as a key site of action for direct diazepam effects. We also show that intra-VTA diazepam infusion increases accumbal dopamine and DOPAC, as well as activity of dopamine D1- but not D2-containing cells. In addition, intra-NAc infusion of a D1-, but not D2, receptor agonist facilitates social dominance and mitochondrial respiration. Conversely, intra-VTA diazepam actions on social dominance and NAc mitochondrial respiration are blocked by pharmacological NAc micro-infusion of a mitochondrial complex I inhibitor or an antagonist of D1 receptors. Our data support the view that diazepam disinhibits VTA dopaminergic neurons, leading to the release of dopamine into the NAc where activation of D1-signaling transiently facilitates mitochondrial function, that is, increased respiration and enhanced ATP levels, which ultimately enhances social competitive behavior. Therefore, our findings critically involve the mesolimbic system in the facilitating effects of diazepam on social competition and highlight mitochondrial function as a potential therapeutic target for anxiety-related social dysfunctions.
The brain circuits of a winner
Social dominance in mice depends on their history of winning in social contests. Zhou et al. found that this effect is mediated by neuronal projections from the thalamus to a brain region called the dorsomedial prefrontal cortex. Selective manipulation of synapses driven by this input revealed a causal relationship between circuit activity and mental effort–based dominance behavior. Thus, synapses in this pathway store the memory of previous winning or losing history.
Science , this issue p. 162
The prefrontal cortex helps adjust an organism's behavior to its environment. In particular, numerous studies have implicated the prefrontal cortex in the control of social behavior, but the neural circuits that mediate these effects remain unknown. Here we investigated behavioral adaptation to social defeat in mice and uncovered a critical contribution of neural projections from the medial prefrontal cortex to the dorsal periaqueductal gray, a brainstem area vital for defensive responses. Social defeat caused a weakening of functional connectivity between these two areas, and selective inhibition of these projections mimicked the behavioral effects of social defeat. These findings define a specific neural projection by which the prefrontal cortex can control and adapt social behavior.
Dopamine-releasing neurons of the ventral tegmental area (VTA) have central roles in reward-related and goal-directed behaviours. VTA dopamine-releasing neurons are heterogeneous in their afferent and efferent connectivity and, in some cases, release GABA or glutamate in addition to dopamine. Recent findings show that motivational signals arising from the VTA can also be carried by non-dopamine-releasing projection neurons, which have their own specific connectivity. Both dopamine-releasing and non-dopamine-releasing VTA neurons integrate afferent signals with local inhibitory or excitatory inputs to generate particular output firing patterns. Various individual inputs, outputs and local connections have been shown to be sufficient to generate reward- or aversion-related behaviour, indicative of the impressive contribution of this small population of neurons to behaviour.
Status alters immune function in macaques
Rhesus macaques experience variable levels of stress on the basis of their position in the social hierarchy. To examine how stress affects immune function, Snyder-Mackler et al. manipulated the social status of individual macaques (see the Perspective by Sapolsky). Social status influenced the immune system at multiple levels, from immune cell numbers to gene expression, and altered signaling pathways in a model of response to infection. Macaques possess a plastic and adaptive immune response wherein social subordination promotes antibacterial responses, whereas high social status promotes antiviral responses.
Science , this issue p. 1041 ; see also p. 967
Status within social hierarchies has great effects on the lives of socially organized mammals. Its effects on human behavior and related physiology, however, is relatively little studied. The present study investigated the impact of military rank on fairness and behavior in relation to salivary cortisol (C) and testosterone (T) levels in male soldiers. For this purpose 180 members of the Austrian Armed Forces belonging to two distinct rank groups participated in two variations of a computer-based guard duty allocation experiment. The rank groups were (1) warrant officers (high rank, HR) and (2) enlisted men (low rank, LR). One soldier from each rank group participated in every experiment. At the beginning of the experiment, one participant was assigned to start standing guard and the other participant at rest. The participant who started at rest could choose if and when to relieve his fellow soldier and therefore had control over the experiment. In order to trigger perception of unfair behavior, an additional experiment was conducted which was manipulated by the experimenter. In the manipulated version both soldiers started in the standing guard position and were never relieved, believing that their opponent was at rest, not relieving them. Our aim was to test whether unfair behavior causes a physiological reaction. Saliva samples for hormone analysis were collected at regular intervals throughout the experiment. We found that in the un-manipulated setup high-ranking soldiers spent less time standing guard than lower ranking individuals. Rank was a significant predictor for C but not for T levels during the experiment. C levels in the HR group were higher than in the LR group. C levels were also elevated in the manipulated experiment compared to the un-manipulated experiment, especially in LR. We assume that the elevated C levels in HR were caused by HR feeling their status challenged by the situation of having to negotiate with an individual of lower military rank. This would be in line with the observation that unequally shared duty favored HR in most cases. We conclude that social status, in the form of military rank affects fairness behavior in social interaction and endocrine levels.
Background
Low socio-economic status (SES) has been found to be associated with a higher prevalence of depression. However, studies that have investigated this association have been limited in their national scope, have analyzed different components of SES separately, and have not used standardized definitions or measurements across populations. The aim of the current study was to evaluate the association between SES and depression across three European countries that represent different regions across Europe, using standardized procedures and measurements and a composite score for SES.
Method
Nationally-representative data on 10,800 individuals aged ≥18 from the Collaborative Research on Ageing in Europe (COURAGE) survey conducted in Finland, Poland and Spain were analyzed in this cross-sectional study. An adapted version of the Composite International Diagnostic Interview was used to identify the presence of depression, and SES was computed by using the combined scores of the total number of years educated (0–22) and the quintiles of the country-specific income level of the household (1–5). Multivariable logistic regression was used to assess the association between SES and depression.
Results
Findings reveal a significant association between depression and SES across all countries (p ≤ 0.001). After adjusting for confounders, the odds of depression were significantly decreased for every unit increase in the SES index for Finland, Poland and Spain. Additionally, higher education significantly decreased the odds for depression in each country, but income did not.
Conclusion
The SES index seems to predict depression symptomatology across European countries. Taking SES into account may be an important factor in the development of depression prevention strategies across Europe.
When individuals engage in social interaction, regardless of the relationship they have with each other and the context within which it occurs (→ Classroom Power; Power in Intergroup Settings), power and dominance are fundamental dimensions that both shape and are shaped by communication (→ Power and Discourse). Studies of how people think about and judge their social relationships have consistently demonstrated the importance of a dominance dimension. People use this dimension to judge and experience their social relationships and the communication that occurs within them (Berger 1994; Ng & Bradac 1993). Judgments concerning who is dominant or submissive or who is “in control” easily come to mind, whether the judgments are made during or after a specific interaction episode or in an ongoing relationship consisting of multiple episodes.
Territorial animals must be able to express social aggression or avoidance in a manner appropriate to spatial context and dominance status. Recent studies indicate that the ventromedial hypothalamus controls both innate aggression and avoidance, suggesting that it may encode an internal state of threat common to both behaviors. Here we used single unit in vivo calcium microendoscopy to identify neurons in the mouse ventromedial hypothalamus encoding social threat. Threat neurons were activated during social defeat as well as when the animal performed risk assessment. Unexpectedly, threat neurons were also activate in the chamber where the animal had been previously defeated and a distinct set of neurons emerged that were active in its home chamber, demonstrating the dynamic encoding of spatial context in the hypothalamus. Ensemble analysis of neural activity showed that social defeat induced a change in the encoding of social information and optogenetic activation of ventromedial hypothalamus neurons was able to elicit avoidance after, but not before social defeat, demonstrating a functional reorganization of the pathway by social experience. These findings reveal how instinctive behavior circuits in the hypothalamus dynamically encode spatial and sensory cues to drive adaptive social behaviors.
Circadian time-keeping mechanisms preserve homeostasis by synchronizing internal physiology with predictable variations in the environment and temporally organize the activation of physiological signaling mechanisms to promote survival and optimize the allocation of energetic resources. In this paper, we highlight the importance of the robust circadian dynamics of allostatic mediators, with a focus on the hypothalamic-pituitary-adrenal (HPA) axis, for the optimal regulation of host physiology and in enabling organisms to adequately respond and adapt to physiological stressors. We review studies showing how the chronic disruption of circadian rhythms can result in the accumulation of allostatic load, which impacts the appropriate functioning of physiological systems and diminishes the resilience of internal systems to adequately respond to subsequent stressors. A careful consideration of circadian rhythm dynamics leads to a more comprehensive characterization of individual variability in allostatic load and stress resilience. Finally, we suggest that the restoration of circadian rhythms after pathological disruption can enable the re-engagement of allostatic mechanisms and re-establish stress resilience.
Background:
The high prevalence and burden to society of drug abuse and addiction is undisputed. However, its conceptualisation as a brain disease is controversial, and available interventions insufficient. Research on the role of stress in drug addiction may bridge positions and develop more effective interventions.
Aim:
The aim of this paper is to integrate the most influential literature to date on the role of stress in drug addiction.
Methods:
A literature search was conducted of the core collections of Web of Science and Semantic Scholar on the topic of stress and addiction from a neurobiological perspective in humans. The most frequently cited articles and related references published in the last decade were finally redrafted into a narrative review based on 130 full-text articles.
Results and discussion:
First, a brief overview of the neurobiology of stress and drug addiction is provided. Then, the role of stress in drug addiction is described. Stress is conceptualised as a major source of allostatic load, which result in progressive long-term changes in the brain, leading to a drug-prone state characterized by craving and increased risk of relapse. The effects of stress on drug addiction are mainly mediated by the action of corticotropin-releasing factor and other stress hormones, which weaken the hippocampus and prefrontal cortex and strengthen the amygdala, leading to a negative emotional state, craving and lack of executive control, increasing the risk of relapse. Both, drugs and stress result in an allostatic overload responsible for neuroadaptations involved in most of the key features of addiction: reward anticipation/craving, negative affect, and impaired executive functions, involved in three stages of addiction and relapse.
Conclusion:
This review elucidates the crucial role of stress in drug addiction and highlights the need to incorporate the social context where brain-behaviour relationships unfold into the current model of addition.
Most socially living species are organized hierarchically, primarily based on individual differences in social dominance. Dominant individuals typically gain privileged access to important resources, such as food, mating partners and territories, whereas submissive conspecifics are often devoid of such benefits. The benefits associated with a high social status provide a strong incentive to become dominant. Importantly, motivational- and reward-related processes are regulated, to a large extent, by the mesolimbic system. Consequently, several studies point to a key role for the mesolimbic system in social hierarchy formation. This review summarizes the growing body of literature that implicates the mesolimbic system, and associated neural circuits, on social hierarchies. In particular, we discuss the neurochemical and pharmacological studies that have highlighted the contributions of the mesolimbic system and associated circuits including dopamine signaling through the D1 or D2 receptors, GABAergic neurotransmission, the androgen receptor system, and mitochondria and bioenergetics. Given that low social status has been linked to the emergence of anxiety- and depressive-like disorders, a greater understanding of the neurochemistry underlying social dominance could be of tremendous benefit for the development of pharmacological treatments to dysfunctions in social behaviors. This article is part of the Special Issue entitled 'The neuropharmacology of social behavior: from bench to bedside'.
The ecological success of the house mouse, Mus musculus domesticus, implies a great capacity to adapt its diet to available food resources. The social transmission of food preference (STFP) is an adaptive type of learning observed in rodents allowing them to enlarge their food repertoire at lower risk by getting olfactory information on novel food sources from conspecifics. This social learning takes place directly, during an encounter with a conspecific or indirectly, via olfactory marks. The objective of this thesis work was to determine how mice use their socio-olfactory environment to make food choices. Our results revealed that the absence of the conspecific during the indirect STFP reduces the social constraints associated with an encounter and allows the acquisition of STFP between unfamiliar conspecifics. However, some physical constraints associated with the perception of information in feces may reduce the availability of food information. We also showed that different sex concerns of individuals may affect the prioritization of information present in feces and limit, in males, the acquisition of STFP. Our results suggest that the use of food information in mice varies according to their social and ecological context and involves different processes such as emotion and attention. Under natural conditions, the direct and indirect STFP could be complementary, each of them extending the conditions for the transmission of food information in rodents.
Dopamine is released in the striatum during development and impacts the activity of Protein Kinase A (PKA) in striatal spiny projection neurons (SPNs). We examined whether dopaminergic neuromodulation regulates activity-dependent glutamatergic synapse formation in the developing striatum. Systemic in vivo treatment with Gαs-coupled G-protein receptors (GPCRs) agonists enhanced excitatory synapses on direct pathway striatal spiny projection neurons (dSPNs), whereas rapid production of excitatory synapses on indirect pathway neurons (iSPNs) required the activation of Gαs GPCRs in SPNs of both pathways. Nevertheless, in vitro Gαs activation was sufficient to enhance spinogenesis induced by glutamate photolysis in both dSPNs and iSPNs, suggesting that iSPNs in intact neural circuits have additional requirements for rapid synaptic development. We evaluated the in vivo effects of enhanced glutamate release from corticostriatal axons and postsynaptic PKA and discovered a mechanism of developmental plasticity wherein rapid synaptogenesis is promoted by the coordinated actions of glutamate and postsynaptic Gαs-coupled receptors.
The μ opioid receptor (MOR) in the nucleus accumbens (NAc) is involved in assigning pleasurable, or hedonic value to rewarding stimuli. Importantly, the hedonic value of a given rewarding stimulus likely depends on an individual's current motivational state. Here, we examined the involvement of MORs in the motivation to interact with a novel or a familiar (cage mate) conspecific in juvenile rats. First, we demonstrated that the selective MOR antagonist CTAP administered into the NAc reduces social novelty preference of juvenile males, by decreasing the interaction time with the novel conspecific and increasing the interaction time with the cage mate. Next, we found that a 3-h separation period from the cage mate reduces social novelty preference in both juvenile males and females, which was primarily driven by an increase in interaction time with the cage mate. Last, we showed that MOR agonism (intracerebroventricularly or in the NAc) restored social novelty preference in juvenile males that did not show social novelty preference following social isolation. Taken together, these data support a model in which endogenous MOR activation in the NAc facilitates the relative hedonic value of novel over familiar social stimuli. Our results may implicate the MOR in neuropsychiatric disorders characterized by altered social motivation, such as major depression and autism spectrum disorder.
The hypothalamo-pituitary-adrenal (HPA) axis comprises interactions between the hypothalamus, the pituitary and the adrenal glands and its activation results in the release of corticosteroid hormones. Corticosteroids are secreted from the adrenal gland in a distinct 24-h circadian rhythm overarching an ultradian rhythm, which consists of hourly corticosteroid pulses exposing target tissues to rapidly changing steroid levels. On top of these rhythms surges can take place after stress. HPA-axis rhythms promote adaptation to predictable (i.e. the earth's rotation) and unpredictable (i.e. stressors) changes in environmental factors. Two steroid hormone receptors, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), are activated by corticosteroids and mediate effects at fast and slow timescales on e.g. glucose availability, gene transcription and synaptic plasticity. The current review discusses the origin of the circadian and ultradian corticosteroid rhythms and their relevance for gene regulation, neuroendocrine and physiological responses to stress and the involvement in the maintenance of brain functionality in rodents.
How environmental and physiological signals interact to influence neural circuits underlying developmentally programmed social interactions such as male territorial aggression is poorly understood. We have tested the influence of sensory cues, social context, and sex hormones on progesterone receptor (PR)-expressing neurons in the ventromedial hypothalamus (VMH) that are critical for male territorial aggression. We find that these neurons can drive aggressive displays in solitary males independent of pheromonal input, gonadal hormones, opponents, or social context. By contrast, these neurons cannot elicit aggression in socially housed males that intrude in another male’s territory unless their pheromone-sensing is disabled. This modulation of aggression cannot be accounted for by linear integration of environmental and physiological signals. Together, our studies suggest that fundamentally non-linear computations enable social context to exert a dominant influence on developmentally hard-wired hypothalamus-mediated male territorial aggression.
Extensive data highlight the existence of major differences in individuals’ susceptibility to stress [1, 2, 3, 4]. While genetic factors [5, 6] and exposure to early life stress [7, 8] are key components for such neurobehavioral diversity, intriguing observations revealed individual differences in response to stress in inbred mice [9, 10, 11, 12]. This raised the possibility that other factors might be critical in stress vulnerability. A key challenge in the field is to identify non-invasively risk factors for vulnerability to stress. Here, we investigated whether behavioral factors, emerging from preexisting dominance hierarchies, could predict vulnerability to chronic stress [9, 13, 14, 15, 16]. We applied a chronic social defeat stress (CSDS) model of depression in C57BL/6J mice to investigate the predictive power of hierarchical status to pinpoint which individuals will exhibit susceptibility to CSDS. Given that the high social status of dominant mice would be the one particularly challenged by CSDS, we predicted and found that dominant individuals were the ones showing a strong susceptibility profile as indicated by strong social avoidance following CSDS, while subordinate mice were not affected. Data from 1H-NMR spectroscopy revealed that the metabolic profile in the nucleus accumbens (NAc) relates to social status and vulnerability to stress. Under basal conditions, subordinates show lower levels of energy-related metabolites compared to dominants. In subordinates, but not dominants, levels of these metabolites were increased after exposure to CSDS. To the best of our knowledge, this is the first study that identifies non-invasively the origin of behavioral risk factors predictive of stress-induced depression-like behaviors associated with metabolic changes.
Dopamine neurons facilitate learning by calculating reward prediction error, or the difference between expected and actual reward. Despite two decades of research, it remains unclear how dopamine neurons make this calculation. Here we review studies that tackle this problem from a diverse set of approaches, from anatomy to electrophysiology to computational modeling and behavior. Several patterns emerge from this synthesis: that dopamine neurons themselves calculate reward prediction error, rather than inherit it passively from upstream regions; that they combine multiple separate and redundant inputs, which are themselves interconnected in a dense recurrent network; and that despite the complexity of inputs, the output from dopamine neurons is remarkably homogeneous and robust. The more we study this simple arithmetic computation, the knottier it appears to be, suggesting a daunting (but stimulating) path ahead for neuroscience more generally. Expected final online publication date for the Annual Review of Neuroscience Volume 40 is July 8, 2017. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
The associations between social status and endogenous testosterone and corticosterone have been well-studied across taxa, including rodents. Dominant social status is typically associated with higher levels of circulating testosterone and lower levels of circulating corticosterone but findings are mixed and depend upon numerous contextual factors. Here, we determine that the social environment is a key modulator of these relationships in Mus musculus. In groups of outbred CD-1 mice living in stable dominance hierarchies, we found no evidence of simple linear associations between social rank and corticosterone or testosterone plasma levels. However, in social hierarchies with highly despotic alpha males that socially suppress other group members, testosterone levels in subordinate males were significantly lower than in alpha males. In less despotic hierarchies, where all animals engage in high rates of competitive interactions, subordinate males had significantly elevated testosterone compared to agonistically inhibited subordinates from despotic hierarchies. Subordinate males from highly despotic hierarchies also had elevated levels of corticosterone compared to alpha males. In pair-housed animals, the relationship was the opposite, with alpha males exhibiting elevated levels of corticosterone compared to subordinate males. Notably, subordinate males living in social hierarchies had significantly higher levels of plasma corticosterone than pair-housed subordinate males, suggesting that living in a large group is a more socially stressful experience for less dominant individuals. Our findings demonstrate the importance of considering social context when analyzing physiological data related to social behavior and using ethologically relevant behavioral paradigms to study the complex relationship between hormones and social behavior.
Individual differences in response to social stress and environmental enrichment may contribute to variability in response to behavioral and pharmacological treatments for drug addiction. In monkeys, social status influences the reinforcing effects of cocaine and the effects of some drugs on cocaine self-administration. In this study, we used male cynomolgus macaques (n=15) living in established social groups to examine the effects of social confrontation on the reinforcing effects of cocaine using a food-drug choice procedure. On the test day, a dominant or subordinate monkey was removed from his homecage and placed into another social pen; 30 min later he was studied in a cocaine-food choice paradigm. For the group, following social confrontation, sensitivity to cocaine reinforcement was significantly greater in subordinate monkeys compared with dominant animals. Examining individual-subject data revealed that for the majority of monkeys (9/15), serving as an intruder in another social group affected cocaine self-administration and these effects were dependent on the social rank of the monkey. For subordinate monkeys, sensitivity to the reinforcing effects of cocaine increased while sensitivity decreased in dominant monkeys. To investigate potential mechanisms mediating these effects, brain glucose metabolism was studied in a subset of monkeys (n=8) using [18F]fluorodeoxyglucose ([18F]FDG) with positron emission tomography. Dominant and subordinate monkeys displayed distinctly different patterns of brain glucose metabolism in their homecage, including areas associated with vigilance and stress/anxiety, respectively, and during social confrontation. These data demonstrate that, depending on an individual's social status, the same social experience can have divergent effects on brain function and cocaine self-administration. These phenotypic differences in response to social conditions support a personalized treatment approach to cocaine addiction.
Behavioral choice is ubiquitous in the animal kingdom and is central to goal-oriented behavior. Hypothalamic Agouti-related peptide (AgRP) neurons are critical regulators of appetite. Hungry animals, bombarded by multiple sensory stimuli, are known to modify their behavior during times of caloric need, rapidly adapting to a consistently changing environment. Utilizing ARCAgRP neurons as an entry point, we analyzed the hierarchical position of hunger related to rival drive states. Employing a battery of behavioral assays, we found that hunger significantly increases its capacity to suppress competing motivational systems, such as thirst, anxiety-related behavior, innate fear, and social interactions, often only when food is accessible. Furthermore, real-time monitoring of ARCAgRP activity revealed time-locked responses to conspecific investigation in addition to food presentation, further establishing that, even at the level of ARCAgRP neurons, choices are remarkably flexible computations, integrating internal state, external factors, and anticipated yield.
Low social status is frequently associated with heightened exposure to social stressors and altered glucocorticoid regulation by the hypothalamic-pituitary-adrenal (HPA) axis. Additionally, personality differences can affect how individuals behave in response to social conditions, and thus may aggravate or protect against the effects of low status on HPA function. Disentangling the relative importance of personality from the effects of the social environment on the HPA axis has been challenging, since social status can predict aspects of behavior, and both can remain stable across the lifespan. To do so here, we studied an animal model of social status and social behavior, the rhesus macaque (Macaca mulatta). We performed two sequential experimental manipulations of dominance rank (i.e., social status) in 45 adult females, allowing us to characterize personality and glucocorticoid regulation (based on sensitivity to the exogenous glucocorticoid dexamethasone) in each individual while she occupied two different dominance ranks. We identified two behavioral characteristics, termed ‘social approachability’ and ‘boldness,’ which were highly social status-dependent. Social approachability and a third dimension, anxiousness, were also associated with cortisol dynamics in low status females, suggesting that behavioral tendencies may sensitize individuals to the effects of low status on HPA axis function. Finally, we found that improvements in dominance rank increased dexamethasone-induced acute cortisol suppression and glucocorticoid negative feedback. Our findings indicate that social status causally affects both behavioral tendencies and glucocorticoid regulation, and that some behavioral tendencies also independently affect cortisol levels, beyond the effects of rank. Together, they highlight the importance of considering personality and social status together when investigating their effects on HPA axis function.