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