Elsevier

Behavioural Brain Research

Volume 371, 3 October 2019, 111991
Behavioural Brain Research

Research report
Noradrenergic and dopaminergic involvement in novelty modulation of aversive memory generalization of adult rats

https://doi.org/10.1016/j.bbr.2019.111991Get rights and content

Abstract

The generalization of aversive memory can be defined as the phenomenon in which a situation similar to (but distinctive from) a previous aversive event triggers an avoidance response. This phenomenon has been suggested to play a role in several psychological disorders. In this study, we investigate the effects of novelty on the generalization of fear memories, and the involvement of noradrenergic and dopaminergic systems in this process. For this study we used male Wistar rats (3 months old, 300–400 g). The participation of each neurotransmitter system was evaluated separately (two set of experiments). In each experimental set, the animals were divided in groups (8 animals each): (i) control, (ii) novelty, and, (iii) antagonist + novelty group (timolol, a β-adrenergic antagonist, or SCH23390, a D1/D5 dopaminergic antagonist, in the first and in the second set of experiments, respectively). Additionaly, to investigate whether novelty exposure increases the levels of noradrenaline and/or dopamine in the hippocampus fifteen animals were divided in three groups (5 animals each).: (i) naïve, (ii) control; and, (iii) novelty. To examine aversive memory, and generalization of aversive memory, we trained adult male Wistar rats in an inhibitory avoidance (IA) memory task and after in a modified inhibitory avoidance (MIA). Before the MIA training some of the animals were exposed to environmental novelty (open field). Immediately before this novelty exposure, some animals received intrahippocampal infusion of timolol (β-adrenergic antagonist), SCH23390 (D1/D5 antagonist) or vehicle to evaluate the involvement of noradrenergic and dopaminergic systems. Finally, to evaluate aversive memory and generalization of aversive memory respectively, half of the animals in each group were tested on IA and half on MIA. We confirmed that the exposure to novelty blocks the generalization of aversive memory, but moreover, demonstrated that this process involves activation of β-adrenergic and dopaminergic D1/D5 pathways. We additionally observed that exposure to novelty raises hippocampal levels of noradrenaline and dopamine. This suggests that these neurotransmitters not only influence long-term memory (LTM) as such, but also aversive memory generalization.

Introduction

The ability to form memories of aversive events is essential for survival [1], since it allows us to deal with the complexity of everyday situations and prepare us for avoidance or defensive action [2]. However, this type of memory is frequently associated with pathologies such as posttraumatic stress (PTSD) and panic disorders [1], since it can lead to exacerbated or inappropriate responses to fear [2,3]. Generalization of aversive memory is thought to be based on the similarity between a current situation and a previous aversive experience [2]. Thus, an individual may avoid a stimulus similar to a previously experienced aversive event [2]. This phenomenon has great adaptive value in a constantly changing environment, but it must be actively controlled to occur only when necessary [2,4,5]. When such control fails, events can be perceived as more dangerous than they actually are, leading to changes in fear control and eventually to pathological fear [2,4,5].

Although generalization of aversive memory is well established, its neural mechanisms have only recently received scientific attention [6]. It is widely accepted that hippocampus is one of the central brain areas that play a role in storage of contextual information, specific to this phenomenon [6]. However, the behavioral and sensory features of generalization are still relatively poorly investigated [5], as well as the mechanisms that may minimize their effects [6]. Strategies that may block the exacerbation of fear responses by reducing generalization could inspire novel treatment possibilities for diseases such as PTSD.

Exposure to a novel environment, during a critical time window, facilitates learning, induces the synthesis of plasticity-related proteins (PRPs), and potentiates the formation of long-term memories [[7], [8], [9]]. This phenomenon is based on the synaptic tagging and capture (STC) hypothesis proposed by Frey and Morris (1997) [10]. The neuromodulatory influence of novelty probably involves a wide variety of brain systems [11], but it has been suggested that PRP synthesis depends especially on adrenergic and dopaminergic systems [[12], [13], [14], [15]]. It is also known that the exposure to new stimuli and environments activates regions such as locus coerulus (LC) and ventral tegmental area (VTA), which control the release of noradrenaline and dopamine, respectively, in different brain areas [[16], [17], [18]]. In addition, our recent study in rats demonstrated that exposure to novelty, prior to exposure to an environment similar to a known aversive environment, avoids generalization of aversive memory, which depends on hippocampal protein synthesis [19]. Considering this background, the aim of this study was to investigate the participation of the noradrenergic and dopaminergic systems in the effect of novelty through a behavioral protocol that induces generalization of aversive memory.

Section snippets

Animals

One hundred and eleven male Wistar rats (3 months old, 300–400 g) were purchased from the Central Vivarium of Federal University of Santa Maria (RS/Brazil). They were housed four per cage and maintained under controlled light and environmental conditions (12 h light/12 h dark cycle at 23 ± 2 °C and 50 ± 10% humidity) with food and water ad libitum. All experiments were conducted in accordance with the “Principles of Laboratory Animal Care” of the National Institutes of Health, and were approved

Noradrenergic system is involved in the modulation of aversive memory generalization by novelty

Animals that were exposed to novelty before MIA on the day following IA training did not display generalization of aversive memory. However, β-adrenergic receptor antagonist (timolol) injection, immediately before novelty exposure, inhibited the novelty effect, suggesting that the effect of novelty on aversive memory generalization depends on the hippocampal noradrenergic system.

On the IA training day, the animals presented no significant difference in step-down latency (H(3) = 2.24;

Discussion

We confirmed that novelty exposure blocks aversive memory generalization, and demonstrated that this process depends on β-adrenergic and D1/D5 dopaminergic pathways. During the IA procedure, all groups were able to recognize the aversive environment, and consequently displayed an avoidance response (higher step-down latency). The initially neutral IA context (conditioned stimulus, CS) pairs or becomes associated with the unconditioned stimulus (US, aversive footshock). The CS context thus

Conclusion

Our set of data confirms that the novelty can modulate the aversive memory generalization and demonstrates the involvement of noradrenaline and the dopamine in the novelty effects.

Authors’ contributions

PBMC, DS, II and RDH defined the study design. LSV and KL performed the behavioral experiments. BR, KL and RR conducted the biochemical analyzes. All authors analyzed and discussed the data and read and approved the final version of the manuscript.

Conflict of interests

The authors declare that there are no conflicts of interests regarding the publication of this manuscript.

Acknowledgments

This work was financed by research grants from the Federal University of Pampa (AGP/Unipampa/Brazil), the National Research Council of Brazil (CNPq/Brazil), the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (PROCAD and Finance Code 001 - CAPES/Brazil), and the Fundação de Amparo à Pesquisa do Rio Grande do Sul (PqG/FAPERGS/RS/Brazil). KL is supported by FAPERGSand CAPES. LSV, II and PBMC are supported by CNPq/Brazil. PBMC is supported by the Women in Science Program from L’Oreal

References (46)

  • R. Adamec et al.

    Neural circuit changes mediating lasting brain and behavioral response to predator stress

    Neurosci. Biobehav. Rev.

    (2005)
  • E. Bignante et al.

    Involvement of septal Cdk5 in the emergence of excessive anxiety induced by stress

    Eur. Pharmacol. J.

    (2008)
  • M. Psyrdellis et al.

    Open field exposure facilitates recovery from an aversive emotional event: involvement of adrenergic and cholinergic transmitter systems

    Neurosci. Lett.

    (2016)
  • J. Lisman et al.

    The hippocampal-VTA loop: controlling the entry of information into long-term memory

    Neuron

    (2005)
  • G. Kastellakis et al.

    Synaptic clustering within dendrites: an emerging theory of memory formation

    Prog. Neurobiol.

    (2015)
  • R.E. Suri et al.

    Modeling functions of striatal dopamine modulation in learning and planning

    Neuroscience

    (2001)
  • M. Costanzi et al.
    (2011)
  • S. Onat et al.

    The neuronal basis of fear generalization in humans

    Nat. Neurosci.

    (2015)
  • K. Huckleberry et al.
    (2016)
  • A. Jasnow et al.

    Perspectives on fear generalization and its implications for emotional disorders

    J. Neurosci. Res.

    (2016)
  • D. Moncada et al.

    Induction of long-term memory by exposure to novelty requires protein synthesis: evidence for a behavioral tagging

    J. Neurosci.

    (2007)
  • J. Myskiw et al.

    Behavioral tagging of extinction learning

    PNAS

    (2013)
  • J. Menezes et al.

    Facilitation of fear extinction by novelty depends on dopamine acting on D1-subtype dopamine receptors in hippocampus

    PNAS

    (2015)
  • Cited by (8)

    • Hippocampal cholinergic receptors and the mTOR participation in fear-motivated inhibitory avoidance extinction memory

      2023, Behavioural Brain Research
      Citation Excerpt :

      In the last 4 days of this recovery period, and before starting the behavioural task, the animals were subjected to four rounds of handling, once daily, which was executed every 24 h [103], to reduce stress, improve the animals’ well-being, decrease the data variability, and improve the experimental reliability [104,105]. Each session of handling consisted of the animal’s transportation from the vivarium to the experimental test room, and gently handling of the animal was performed for 5 min by the experimenter [105]. To evaluate the avoidance extinction memory, the task that was chosen was passive step-down inhibitory avoidance (IA), a fear-motivated and instrumental paradigm.

    • Intermediates of α-synuclein aggregation: Implications in Parkinson's disease pathogenesis

      2022, Biophysical Chemistry
      Citation Excerpt :

      Along with the phosphorylated forms, N-terminal acetylated forms of α-Syn have been observed in LBs from DLB patients [182,193]. Recent studies suggest that N-terminal acetylation reduces α-Syn oligomerization induced by DOPAL (3,4-Dihydroxyphenylacetaldehyde), a toxic dopamine metabolite [194]. N-terminal acetylation is also demonstrated to be essential for the appropriate binding / interactions of the plasma membrane with α-Syn [195].

    • Effect of short- and long-term heat exposure on brain monoamines and emotional behavior in mice and rats

      2021, Journal of Thermal Biology
      Citation Excerpt :

      Moreover, the NA level in the hippocampus is increased by short-term heat exposure (Lieberman et al., 2005). Increased NA level in the hippocampus is related to memory (Lima et al., 2019). It is considered that increasing NA level in the hippocampus following heat exposure might maintain the memory function.

    View all citing articles on Scopus
    View full text