Latency to Reward Predicts Social Dominance in Rats: A Causal Role for the Dopaminergic Mesolimbic System

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.

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

Laura Lozano Montes

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.

EPFL2015

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

Neurobiological Mechanisms Involved in the Establishment and Maintenance of Dominance Hierarchies and its Modulation by Stress in Rats

Maria del Carmen Sandi Perez, Marjan Timmer

Stress can have a strong and long lasting effect on the establishment and maintenance of dominance hierarchies in rats. When two rats of a pair have not been stressed (non-stressed pair) before a first social encounter, they establish a dominance hierarchy, but the rank that is obtained during this first encounter is not maintained until a second encounter one week later. When one rat of the pair is stressed (stressed pair) before the first encounter, the stressed rat becomes subordinate during the first encounter and the hierarchy that is formed is long lasting and stable. In this thesis, the neurobiological mechanisms underlying the effects of stress on dominance hierarchies were studied. In the first study, we investigated the role of increasing corticosterone levels before or just after a first encounter between two rats of a pair in the establishment and the long-term maintenance of a dominance hierarchy. We show that pre-social encounter corticosterone treatment does not affect the outcome of the hierarchy during a first encounter, but induces a long-term memory for the hierarchy when the corticosterone-injected rat becomes dominant during the encounter, but not when it becomes subordinate. Post-social encounter corticosterone leads to a long-term maintenance of the hierarchy only when the subordinate rat of the pair is injected with corticosterone. This corticosterone effect implicates glucocorticoids in the consolidation of the memory for a recently established hierarchy. Next, we investigated the immediate and long-term changes in mRNA levels of receptors for oxytocin and vasopressin in medial amygdala and lateral septum. In subordinate rats of the stressed pairs, we found a downregulation in oxytocin receptor mRNA in medial amygdala at three hours after the first encounter, and a downregulation in vasopressin 1a receptor mRNA in lateral septum one week after the first encounter. We show that administration of an oxytocin antagonist in the medial amygdala of the subordinate rat immediately after a first encounter induces a long-term memory for the established hierarchy. Administration of a vasopressin 1a receptor antagonist in the lateral septum of the subordinate rat just before a second encounter mimics the effects of exposure to acute stress on the long-term establishment of a dominance hierarchy. These results suggest a role for oxytocin and vasopressin in the effects of stress on the long-term establishment of dominance hierarchies. Finally, we investigated the long-term effects of acute stress and hierarchy formation on the establishment of a second hierarchy with an unfamiliar opponent. We show that the behavior of stressed subordinate rats towards an unfamiliar opponent depends on the previous status of the opponent: when paired with a previously dominant rat they become subordinate, whereas they become dominant when paired with a previously subordinate rat. Furthermore, we show that monoamine oxidase A and androgen receptor mRNA levels are downregulated in the lateral septum of stressed subordinate rats at one week after the first encounter; i.e., at the time when we have observed their flexible social behavior against unfamiliar opponents. The monoamine oxidase A inhibitor clorgyline was injected into the lateral septum to examine whether there was a causal relationship between changes in monoamine oxidase A mRNA levels and offensive behavior towards an unfamiliar subordinate opponent. However, our results did not support this hypothesis. Taken together, we have shown that exposure to acute stress and a social encounter leads to changes in the mRNA levels of receptors for oxytocin, vasopressin and androgens and of monoamine oxidase A. These changes might underlie the effect of stress on the formation of a stable and long-lasting dominance hierarchy. Corticosterone plays a role in the long-term maintenance of the recently established hierarchy and hence it is an ideal candidate to mediate some of the observed neurobiological changes.

EPFL2011