Naturalistic housing condition promotes behavioral flexibility and increases resilience to stress in rats.

Behavioral flexibility is an indispensable cognitive ability that allows the adjustment of behavioral responses to different situations, while resilience refers to the capability to deal effectively with stress. On one hand, standard laboratory housing provides impoverished cognitive, sensory, and physical stimulation compared to the conditions found in nature. Conversely, enriched and naturalistic housing conditions offer a broadening in the behavioral repertoire that can be depicted by the animals in their home cages, in addition to enabling a better management of possible stressors. Here, we investigated the effects of environmental enrichment and naturalistic housing compared to the standard laboratory housing on different behavioral tasks, including Morris water maze, open field, object location, and fear conditioning. This allowed us to evaluate how different housing conditions modulate behavioral flexibility and resilience to stress, in addition to spatial memory, in adult male rats. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Distinct engrams control fear and extinction memory.

Memories are stored in engram cells, which are necessary and sufficient for memory recall. Recalling a memory might undergo reconsolidation or extinction. It has been suggested that the original memory engram is reactivated during reconsolidation so that memory can be updated. Conversely, during extinction training, a new memory is formed that suppresses the original engram. Nonetheless, it is unknown whether extinction creates a new engram or modifies the original fear engram. In this study, we utilized the Daun02 procedure, which uses c-Fos-lacZ rats to induce apoptosis of strongly activated neurons and examine whether a new memory trace emerges as a result of a short or long reactivation, or if these processes rely on modifications within the original engram located in the basolateral amygdala (BLA) and infralimbic (IL) cortex. By eliminating neurons activated during consolidation and reactivation, we observed significant impacts on fear memory, highlighting the importance of the BLA engram in these processes. Although we were unable to show any impact when removing the neurons activated after the test of a previously extinguished memory in the BLA, disrupting the IL extinction engram reactivated the aversive memory that was suppressed by the extinction memory. Thus, we demonstrated that the IL cortex plays a crucial role in the network involved in extinction, and disrupting this specific node alone is sufficient to impair extinction behavior. Additionally, our findings indicate that extinction memories rely on the formation of a new memory, supporting the theory that extinction memories rely on the formation of a new memory, whereas the reconsolidation process reactivates the same original memory trace.

Molecular mechanisms underpinning deconditioning-update in fear memory.

Traumatic experiences are closely associated with some psychiatric conditions such as post-traumatic stress disorder. Deconditioning-update promotes robust and long-lasting attenuation of aversive memories. The deconditioning protocol consists of applying weak/neutral footshocks during reactivations, so that the original tone-shock association is replaced by an innocuous stimulus that does not produce significant fear response. Here, we present the molecular bases that can support this mechanism. To this end, we used pharmacological tools to inhibit the activity of ionotropic glutamate receptors (NMDA-GluN2B and CP-AMPA), the activity of proteases (calpains), and the receptors that control intracellular calcium storage (IP3 receptors), as well as the endocannabinoid system (CB1). Our results indicate that blocking these molecular targets prevents fear memory update by deconditioning. Therefore, this study uncovered the molecular substrate of deconditioning-update strategy, and, broadly, shed new light on the traumatic memory destabilization mechanisms that might be used to break the boundaries regarding reconsolidation-based approaches to deal with maladaptive memories.

Characterization of deconditioning-update on fear memory attenuation.

Fear memory expression can be attenuated by updating the footshock perception during the plastic state induced by retrieval, from a strong unconditioned stimulus to a very weak one through deconditioning. In this process, the original fear association of the conditioned stimulus with the footshock is substituted by an innocuous stimulus and the animals no longer express a fear response. In the present study, we explore the boundaries of this deconditioning-update strategy by the characterization of this phenomenon. We found that there is an optimal mismatch between the footshock intensity delivered in the training and in the reactivation. Likewise, we characterized the temporal window that the protocol is efficient in hindering fear response. Our findings contribute to a better understanding of the limits in which deconditioning acts in attenuating fear memory, so that an optimized protocol using this strategy can be planned in order to deal with emotional disorders.

Gamma-decanolactone attenuates acute and chronic seizures in mice: a possible role of adenosine A1 receptors.

This study aimed to investigate the possible gamma-decanolactone mechanisms of action in the GABAergic and adenosine systems using the aminophylline-induced acute crisis model and the pentylenetetrazole-induced kindling model. In the acute model, male mice received administration of bicuculline (GABAA receptor antagonist), 8-cyclopentyl-1,3-dipropylxanthine (A1 receptor antagonist) or ZM241385 (A2A receptor antagonist), 15 min before the treatment with gamma-decanolactone (300 mg/kg). After a single dose of aminophylline was administered, the animals were observed for 60 min. In the chronic model of seizure, 30 min after the treatment with gamma-decanolactone, mice received pentylenetetrazole once every third day. On the last day of kindling, the animals received the same GABA and adenosine antagonists used in the acute model, 15 min before gamma-decanolactone administration. The protein expression of GABAA α1 receptor and adenosine A1 receptor was detected using western blotting technique in hippocampal samples. The results showed that gamma-decanolactone increased the latency to first seizure and decreased seizure occurrence in the acute and chronic models. The adenosine A2A receptor antagonist and GABAA receptor antagonist were not able to change gamma-decanolactone behavioral seizure induced by aminophylline or pentylenetetrazole. The administration of adenosine A1 receptor antagonist reversed the protective effect of gamma-decanolactone in both models. In addition, gamma-decanolactone promoted an increase in the expression GABAA α1 receptor, in the hippocampus. The results suggest that the neuroprotective effect of gamma-decanolactone observed during the investigation could have a straight connection to its action on A1 adenosine receptors.

Rosmarinic acid improves oxidative stress parameters and mitochondrial respiratory chain activity following 4-aminopyridine and picrotoxin-induced seizure in mice.

Studies have indicated that epilepsy, an important neurological disease, can generate oxidative stress and mitochondrial dysfunction, among other damages to the brain. In this context, the use of antioxidant compounds could provide neuroprotection and help to reduce the damage caused by epileptic seizures and thereby the use of anticonvulsant drugs. Rosmarinic acid (RA) is an ester of caffeic acid and 3,4-dihydroxyphenylactic acid that prevents cell damage caused by free radicals, acting as an antioxidant. It also presents anti-inflammatory, antimutagenic, and antiapoptotic properties. In this work, we used two models of acute seizure, 4-aminopyridine (4-AP) and picrotoxin (PTX)-induced seizures in mice, to investigate the anticonvulsant, antioxidant, and neuroprotective profile of RA. Diazepam and valproic acid, antiepileptic drugs already used in the treatment of epilepsy, were used as positive controls. Although RA could not prevent seizures in the models used in this study, neither enhance the latency time to first seizure at the tested doses, it exhibited an antioxidant and neuroprotective effect. RA (8 and 16 mg/kg) decreased reactive oxygen species production, superoxide dismutase activity, and DNA damage, measured in hippocampus, after seizures induced by PTX and 4-AP. Catalase activity was decreased by RA only after seizures induced by 4-AP. The activity of the mitochondrial complex II was increased by RA in hippocampus samples after both seizure models. The results obtained in this study suggest that RA is able to reduce cell damage generated by the 4-AP and PTX seizures and therefore could represent a potential candidate in reducing pathophysiological processes involved in epilepsy.