Elsevier

Neuroscience

Volume 248, 17 September 2013, Pages 436-447
Neuroscience

Differential impact of a complex environment on positive affect in an animal model of individual differences in emotionality

https://doi.org/10.1016/j.neuroscience.2013.06.015Get rights and content

Highlights

  • bHRs emit more 50-kHz USVs relative to bLRs when exposed to a novel environment.

  • The presence of a cagemate increases 50-kHz USVs in both bHRs and bLRs.

  • Acute EC increases USVs, in bHRs, whereas chronic exposure decreases USVs in bHRs.

  • bLRs require repeated exposure to EC to show a significant increase in USVs.

Abstract

Anhedonia, or the inability to experience positive feelings is a hallmark of depression. However, few animal models have relied on decreased positive affect as an index of susceptibility to depression. Rats emit frequency-modulated ultrasonic vocalizations (USVs), designated as “positive” calls in the 50-kHz range. USVs have been associated with pharmacological activation of motivational reward circuits. Here we utilized selectively-bred rats differing in “emotionality” to ask whether there are associated differences in USVs. Rats bred based on locomotor response to novelty and classified as bred High Responders (bHRs) or bred Low Responders (bLRs) exhibit inborn differences in response to environmental cues, stress responsiveness, and depression-like behavior. These animals also exhibit differences in anxiety-like behavior, which are reversed by exposure to environmental complexity (EC). Finally, these animals exhibit unique profiles of responsiveness to rewarding stimuli accompanied with distinct patterns of dopamine regulation. We investigated whether acute and chronic environmental manipulations impacted USVs in bHRs and bLRs. We found that, relative to bLRs, bHRs emitted significantly more 50-kHz USVs. However, if a bLR is accompanied by another bLR, there is a significant increase in 50-kHZ USVs emitted by this phenotype. bHRs emitted increases in 50-kHZ UVSs upon first exposure to EC, whereas bLRs showed a similar increase only after repeated exposure. bLRs’ increase in positive affect after chronic EC was coupled with significant positive correlations between corticosterone levels and c-fos mRNA in the accumbens. Conversely, a decline in the rate of positive calls in bHRs after chronic EC was associated with a negative correlation between corticosterone and accumbens c-fos mRNA. These studies demonstrate that inborn differences in emotionality interact with the environment to influence positive affect and underscore the potential interaction between glucocorticoids and the mesolimbic reward circuitry in modulating 50-kHz calls.

Introduction

Major Depressive Disorder (MDD) is a clinical state characterized by unrelenting negative mood and the inability to experience positive thoughts and emotions. Consequently, efforts examining the neurobiology of depression have focused on animal models of negative affect, with a remaining major gap concerning the neurobiology of anhedonia as a core symptom of major depression. Advances have been made toward studying positive affect, however, our understanding of the neural circuitry of positive behaviors stems primarily from studies of reward mechanism—e.g. in response to food or drugs of abuse. These studies do not typically consider the spontaneous propensity to react positively to environmental stimuli, nor the role of physical and social features of the environment in triggering positive affective responses, or lack thereof, as seen in depressed individuals. Yet, basal differences in affective responsiveness likely lie at the core of vulnerability to mood and anxiety disorders. Addressing the question of propensity for positive affect vs. anhedonia requires a means of detecting positive affect as well as a validated animal model of differential vulnerability to anxiety- and depression-like behavior.

For more than 10 years, the measurement of 50-kHz ultrasonic vocalizations (USVs) has offered a valuable index of positive affect in rodents (Burgdorf and Panksepp, 2006). Thus, frequency-modulated 50-kHz calls have been associated with positive valence, and are reliably elicited during, and in anticipation of, various rewarding stimuli including food, sex and brain stimulation (Burgdorf et al., 2000) For example amphetamine administered either intraventricularly or directly into the shell of the nucleus accumbens (NAcc) increases 50-kHz USVs (Burgdorf et al., 2001). Thus, the mesocorticolimbic reward circuitry has been proposed to underlie 50-kHz USV calling and its associated positive state (Burgdorf et al., 2007). Here we will focus on USVs as a measure of positive affect and investigate its neural correlates in an animal model of differential reactivity to environmental stimuli.

Animals selectively bred based on their response to a novel environment, bred High Responders (bHRs) and Low Responders (bLRs), are characterized by significant differences in emotional reactivity. Thus bLRs, which are characterized by low exploration when exposed to a novel environment, are more prone to exhibit negative affect including high anxiety and increased depression-like behavior (Garcia-Fuster et al., 2012, Stead et al., 2006, Perez et al., 2009, Stedenfeld et al., 2011). Interestingly, repeated exposure to environmental complexity (EC) selectively benefits bLRs by reducing their anxiety-like behavior (Perez et al., 2009). However, it has yet to be determined whether the benefits of EC to bLRs’ emotionality are also manifested as increases in positive affect.

Beyond reducing anxiety, EC is known to have antidepressant effects (Llorens-Martin et al., 2011, Hendriksen et al., 2012) and confer stress resilience in several animal models of depression (Lehmann and Herkenham, 2011). Moreover, several brain regions including the infralimbic cortex, prelimbic cortex, and nucleus accumbens have been implicated in resilience mechanisms. EC has also been shown to positively influence antidepressant outcome response in mice exposed to chronic stress (Branchi et al., 2013). Still, while the mechanisms of EC have mostly been attributed to mitigating stress reactivity (Schloesser et al., 2010), it is not known whether EC has any impact on modulating positive affect.

The bHR and bLR lines also differ in reward signaling pathways. In particular, bHRs exhibit a higher frequency of spontaneous dopamine ‘release events’, enhanced dopamine (DA) response to reward-associated cues, and elevated sensitivity to dopamine agonists (Flagel et al., 2010, Flagel et al., 2011). Moreover, bHRs show greater psychomotor sensitization to repeated cocaine treatment (Garcia-Fuster et al., 2010) and increased motivation to take cocaine (Cummings et al., 2011).

In the current study we ask whether bHR and bLR rats exhibit differences in positive affect and whether the reward circuit may be implicated in affective responses to the environment in these animals. We first examined whether bHRs and bLRs exhibited individual differences in 50-kHz USVs and determined the extent to which this measure could be altered by changes in the environment. Environmental manipulations included altering social group experience and increasing environmental complexity under acute and chronic conditions. Neural correlates of positive affect were studied by using c-fos in situ hybridization in the shell and core of the Nucleus Accumbens and in other regions implicated in reward including the infralimbic and prelimbic medial prefrontal cortex (mPFC) (Cardinal et al., 2002) and the dorsal and ventral periaqueductal gray matter (dPAG and vPAG) (Olmstead and Franklin, 1997). We also analyzed corticosterone (CORT) levels after the acute and chronic experimental manipulations. As CORT levels increase in conjunction with behavioral responses to rewarding stimuli such as cocaine and opiates (Marinelli and Piazza, 2002), we hypothesized that increased USVs would be associated with increases in CORT levels.

Section snippets

Animals

Adult Male Sprague–Dawley rats were obtained from our in-house breeding colony at the Molecular and Behavioral Neuroscience Institute (MBNI) where we have maintained the bHR–bLR lines for over 35 generations. bHR–bLR lines are selectively bred based on differences in exploratory response to novelty, a trait initially used to predict individual differences in drug-taking behavior (Piazza et al., 1989). A detailed description of the breeding strategy and behavioral characterization of the bHR–bLR

bHRs emit a higher number of frequency-modulated 50-kHz calls relative to bLRs

Given that bHRs and bLRs have been selectively bred based on individual differences in locomotor response to novelty, we first determined whether they exhibit differences in the number of FM 50-kHz USV calls outside of their home cage. As presented in Fig. 2A, bHRs show a significantly higher number of 50-kHz calls relative to bLRs under these conditions [t(10) = 2.7, p = 0.02].

  • (a)

    Acute exposure to a complex environment increases the number of frequency-modulated 50-kHz calls in bHRs, but not bLRs.

  • (b)

Discussion

The current studies were aimed at uncovering whether bHRs and bLRs rats, which show innate differences in negative affect-related behaviors (Garcia-Fuster et al., 2012, Stead et al., 2006) and differences in accumbens response to the rewards and environmental stimuli (Flagel et al., 2011), displayed differences in positive affect. Given that the nucleus accumbens has been proposed as a mediator of USVs (Burgdorf et al., 2007) we explored whether accumbens c-fos activation was associated with

Conclusion

Our studies suggest that the environment differentially modulates inborn differences in positive affect between bHRs and bLRs, and highlight the relationship bewteen glucocorticoid levels and neuronal activity in the nucleus accumbens as a potential mediating mechanism.

Acknowledgements

We are grateful to James Stewart, Sarah Wong, Andrea Betrus and Krystin Harper for technical assistance.

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    This research was supported by NIMH 20030 (JAPS), NIDA P01 DA021633 (HA) and Office of Naval Research (ONR) N00014-09-1-0598 (HA) and Hope for Depression Research Foundation (HDRF) RGA 10-011 (HA). MJGF is a ‘Ramón y Cajal’ Researcher (MINECO-UIB).

    These authors contributed equally to this publication.

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