The impact of anxiety and reward-seeking traits on social competition and the role of the mesolimbic dopaminergic system

Laura Lozano Montes
EPFL, 2015
EPFL thesis

Abstract

Social hierarchies are established across a range of different taxa in the animal kingdom. Given that hierarchy inequalities are highly present in nowadays society and the health problems that low rank individuals suffer from this, it is surprising that not much is known about the underlying neurobiological mechanisms that predispose an individual to become dominant or submissive. We aimed to have a better understanding of personality-related factors (such as anxiety and reward-seeking behaviors) and underlying brain mechanisms that predispose rats to become dominant. We aimed to study the neurobiological mechanisms involved in the modulation of dominance by anxiety. Peripheral injection of anxiolytic drugs has been shown to modulate the dopaminergic mesolimbic system by acting in the GABAergic neurons on the ventral tegmental area (VTA). Our studies specifically targeted GABAergic receptors within the VTA modulating both anxiety and dominance. However, the activation of GABAergic receptors in the nucleus accumbens (NAc) affected dominance but had no effect on anxiety. Furthermore, we found that the NAc is required for the effects of the anxiolytic diazepam on the establishment of social dominance. We assessed potential differences on the accumbal dopaminergic system in relation to anxiety. To this end, we assessed catecholamines levels by high performance liquid chromatography (HPLC) and confirmed the existence of differences in accumbal dopamine content between high and low anxious rats. Subsequently, we showed that pharmacological activation of D1 receptors within the NAc enhanced social dominance. In addition, activation of GABAergic receptors in the VTA, in addition to enhancing social dominance, enhanced the accumbal dopaminergic system. These findings lead us to hypothesize a critical role on the observed behavioral effects for the firing of the VTA dopaminergic neurons that project to the NAc. Subsequently, we investigated the consequences of phasically activating VTA dopaminergic neurons projecting to the NAc in a social competition test. To specifically modulate firing properties of dopaminergic neurons within the VTA of behaving animals, we performed optogenetic activation in TH::Cre rats infused with Cre-dependent virus expressing channelrhodopsin-2 (ChR2). Our results showed that phasic activation of the VTA dopaminergic neurons during the social competition test for palatable rewards was not sufficient to modify the output of the encounters. Winners of the social competition tests were found to have a trend for higher reward-seeking phenotype (lower latencies to get rewards on their last day of individual training) which leads us to subsequently study the role of reward-seeking trait on the rank attained in a social hierarchy. Our data indicates a role for reward-seeking behaviors during last day of individual training (on social competition for palatable rewards test) on the output of several social competition tests. Interestingly, the combination of phasic optical activation of VTA dopaminergic neurons during the last two days of training and during social competition increased dominance. Altogether, our studies have elucidated the effects of anxiety and reward-seeking traits on rat's hierarchy establishment. Furthermore, we were able to modulate the output of a social competition test by optical activations of the mesolimbic dopaminergic system.

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Laura Lozano Montes
EPFL, 2015
EPFL thesis

Abstract

Official source

https://infoscience.epfl.ch/record/209273?ln=en

About this result

Related concepts (19)

Competition is a rivalry where two or more parties strive for a common goal which cannot be shared: where one's gain is the other's loss (an example of which is a zero-sum game). Competition can ari

The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the nucleus accumbens septi, Latin for "nucleus adjacent to the septum") is a region in the basal forebrain ro

Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine

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Related publications (13)

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Dopaminergic fiber protection and regeneration by Wlds protein and GDNF in rodent models of Parkinson disease

Ali Etemad-Sajadi

Parkinson disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. The resulting failure of the nigrostriatal pathway leads to profound dopamine deficiency, causing bradykinesia, tremor, rigidity and postural imbalance. The current therapeutic options for this disabling disorder remain symptomatic and are devoid of any impact on the neurodegeneration process per se. The development of neuroprotective and regenerative strategies constitute therefore an important challenge, in order to halt and possibly reverse the loss of the nigrostriatal pathway in PD. In the present study, we have investigated two different approaches to protect or restore the nigrostriatal dopaminergic system in rodent models of PD. In the first part, we examined the potential of a spontaneous dominant mutation in mice called slow Wallerian degeneration (Wlds) to confer protection of the dopaminergic pathway against the catecholaminergic toxin 6-hydroxydopamine (6-OHDA). Interestingly, the Wlds fusion protein proved capable to provide functional preservation of the nigrostriatal dopaminergic terminals. The observed Wlds-mediated protection of dopaminergic axons might help to further elucidate the mechanisms leading to the loss of dopamine axons in PD and conduct to the development of new therapeutic modalities for this disorder. In the second approach, we assessed the protective and regenerative potential of the neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) delivered via capsules in a rat model of PD. GDNF delivery by encapsulated cells resulted in regeneration of dopaminergic fibers and behavioral improvement in a bilateral 6-OHDA model in the rat. Importantly, GDNF withdrawal did not affect the morphological and behavioral effects in our model. The sustainability of the striatal dopaminergic reinnervation and behavioral performances following GDNF washout has important implications. It suggests that GDNF needs to be delivered only transiently to allow prolonged functional regenerative effect, rendering the retrievable capsules attractive to achieve this purpose in PD patients. The promising potential of GDNF to protect and regenerate the nigrostriatal pathway has been hampered by several recent studies showing that long-term GDNF overexpression in the intact nigrostriatal pathway induces a downregulation of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of dopamine. In the last part of this work, we aimed therefore at investigating the effect of GDNF on other enzymes of dopamine biosynthesis, using a lentiviral vector-mediated gene transfer technique, in order to overexpress GDNF in rat striatum. We showed that in addition to TH downregulation, long-term GDNF overexpression results in tetrahydrobiopterin upregulation, and importantly in dopamine decrease in the intact striatum of rats. In a clinical perspective, dose and treatment duration of the trophic factor will thus have to be established and optimized with the aim of achieving beneficial neuroprotective effects while circumventing undesirable pharmacologic effects on dopamine biosynthesis. The discovery of new protective molecules such as the Wlds protein, as well as a better understanding of cellular effects of the promising neurotrophic factor GDNF might lead to the establishment of neuroprotective and neuroregenerative strategies for PD in the close future.

EPFL2005

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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

Nature Publishing Group2018

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Reward signals encoded in the mesolimbic dopaminergic system guide approach/seeking behaviors to all varieties of life-supporting stimuli (rewards). Differences in dopamine (DA) levels have been found between dominant and submissive animals. However, it is still unclear whether these differences arise as a consequence of the rewarding nature of the acquisition of a dominant rank, or whether they preexist and favor dominance by promoting reward-seeking behavior. Given that acquisition of a social rank determines animals’ priority access to resources, we hypothesized that differences in reward-seeking behavior might affect hierarchy establishment and that modulation of the dopaminergic system could affect the outcome of a social competition. We characterized reward-seeking behaviors based on rats’ latency to get a palatable-reward when given temporary access to it. Subsequently, rats exhibiting short (SL) and long (LL) latency to get the rewards cohabitated for more than 2 weeks, in order to establish a stable hierarchy. We found that SL animals exhibited dominant behavior consistently in social competition tests [for palatable-rewards and two water competition tests (WCTs)] after hierarchy was established, indicating that individual latency to rewards predicted dominance. Moreover, because SL animals showed higher mesolimbic levels of DA than LL rats, we tested whether stimulation of mesolimbic DA neurons could affect the outcome of a social competition. Indeed, a combination of optical stimulation of mesolimbic DA neurons during individual training and during a social competition test for palatable rewards resulted in improved performance on this test.

2019

Dopaminergic fiber protection and regeneration by Wlds protein and GDNF in rodent models of Parkinson disease

Ali Etemad-Sajadi

EPFL2005