Hippocampal noradrenergic activation is necessary for object recognition memory consolidation and can promote BDNF increase and memory persistence.

Previously we showed that activation of the Nucleus of the Solitary Tract (NTS)-Nucleus Paragigantocellularis (PGi)-Locus coeruleus (LC) pathway, which theoretically culminates with norepinephrine (NE) release in dorsal hippocampus (CA1 region) and basolateral amygdala (BLA) is necessary for the consolidation of object recognition (OR) memory. Here we show that, while the microinjection of the beta-noradrenergic receptor blocker timolol into CA1 impairs OR memory consolidation, the microinjection of norepinephrine (NE) promotes the persistence of this type of memory. Further, we show that OR consolidation is attended by an increase of norepinephrine (NE) levels and of the expression of brain derived neurotrophic factor (BDNF) in hippocampus, which are impaired by inactivation of the NTS-PGi-LC pathway by the infusion of muscimol into the NTS.

Novelty facilitates the persistence of aversive memory extinction by dopamine regulation in the hippocampus and ventral tegmental area.

Aversive memory extinction comprises a novel learning that blocks retrieving a previously formed traumatic memory. In this sense, aversive memory extinction is an excellent tool for decreasing fear responses. However, this tool it's not effective in the long term because of original memory spontaneous recovery. Thus, searching for alternative strategies that strengthen extinction learning is essential. In the current study, we evaluated the effects of a novel context (i.e., novelty) exposure on aversive memory extinction enhancement over days and the dopaminergic system requirement. Given the purpose, experiments were conducted using 3-month-old male Wistar rats. Animals were trained in inhibitory avoidance (IA). Twenty-four hours later, rats were submitted to a weak extinction protocol. Still, 30 min before the first extinction session, animals were submitted to an exploration of a novel context for 5 min. After, memory retention and persistence were evaluated 24 h, 3, 7, 14, and 21 days later. The exposition of a novel context caused a decrease in aversive responses in all days analyzed and an increase in dopamine levels in the hippocampus. The intrahippocampal infusion of dopamine in the CA1 area or the stimulation of the ventral tegmental area (VTA) by a glutamatergic agonist (NMDA) showed similar effects of novelty. In contrast, VTA inhibition by a gabaergic agonist (muscimol) impaired the persistence of extinction learning induced by novelty exposition and caused a decrease in hippocampal dopamine levels. In summary, we show that novel context exposure promotes persistent aversive memory extinction, revealing the significant role of the dopaminergic system.

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

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 ß-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 (ß-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 ß-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.

One-single physical exercise session after object recognition learning promotes memory persistence through hippocampal noradrenergic mechanisms.

Previously we showed the involvement of the hippocampal noradrenergic system in the consolidation and persistence of object recognition (OR) memory. Here we show that one-single physical exercise session performed immediately after learning promotes OR memory persistence and increases norepinephrine levels in the hippocampus. Additionally, effects of exercise on memory are avoided by an intra-hippocampal beta-adrenergic antagonist infusion. Taken together, these results suggest that exercise effects on memory can be related to noradrenergic mechanisms and acute physical exercise can be a non-pharmacological intervention to assist memory consolidation and persistence, with few or no side effects.