Effects of orexin-a receptor blockade on memory facilitation by intracranial self-stimulation
- Autores: Soleil Garcia Brito
- Directores de la Tesis: Laura Aldavert i Vera (dir. tes.), Pilar Segura i Torres (dir. tes.), Gemma Huguet Blanco (dir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2018
- Idioma: español
- Tribunal Calificador de la Tesis: Osvaldo Giorgi (presid.), Margalida Coll (secret.), Francisco Claro Izaguirre (voc.)
- Programa de doctorado: Programa Oficial de Doctorado en Neurociencias
- Materias:
- Enlaces
- Tesis en acceso abierto en: TESEO
- Resumen
Intracranial self-stimulation (ICSS) has been shown to facilitate implicit and explicit memory. In order to explain the facilitating effects of ICSS on learning and memory, several mechanisms have been proposed. Firstly, ICSS promotes structural plasticity and the expression of plasticity-related genes in the hippocampus and other memory-related structures. In addition, ICSS boosts general arousal states through the activation of many excitatory neurotransmission systems involved in learning and memory. However, research exploring the implication of the excitatory orexinergic system in the facilitative effects of ICSS on memory has yet to be carried out.
The orexinergic system plays a role in homeostatic regulation, food intake and the regulation of the sleep-wake cycle. Orexin-A and its selective receptor OX1R are involved in processes that overlap with those affected by ICSS. For instance, orexin-A participates in reward processing through interactions with the dopaminergic system in several reward-related regions. Moreover, orexin-A is implicated in the regulation of arousal states through the stimulation of the noradrenergic and cholinergic systems. In addition, OX1R action within the cholinergic system also modulates attentional processing. Finally, orexin-A and OX1R have been gaining relevance with regard to learning and memory processes, in that orexin-A administration facilitates the acquisition of several types of memory. Interestingly, the orexinergic neurons are located in the lateral hypothalamus, which is also where the highest rates of ICSS behavior are recorded.
In order to study the relationship between the orexinergic system and the facilitating effect of ICSS on learning and memory, this dissertation presents four studies which set out to explore whether or not blocking OX1R, using SB-334867, affects said facilitating effects on two different memory tasks. Specifically, the effects of ICSS and OX1R blockade were studied in a standard spatial version of the Morris Water Maze (MWM) and an adapted version of a simultaneous visual discrimination (SVD) implicit task using the same apparatus.
Study I and Study II served as preparatory experiments to 1) examine the effects of ICSS on a SVD task, and 2) characterize the training protocol in which the SB-334867 would result in impaired spatial learning and memory. We found that ICSS facilitates the acquisition and retention of an SVD task, while promoting an inflexible discrimination memory; and that SB-334867 deteriorates spatial learning only in a weak training condition.
In Study III, we used the previously characterized training protocol to assess the effects of OX1R blockade on the facilitating effects of ICSS on a spatial memory task in the MWM. The level of c-Fos expression in memory-related areas of the thalamo-cortico-hippocampal system was also measured. Study IV evaluated the effects of OX1R blockade on the facilitation of an SVD task in the MWM caused by ICSS, as well as the acetycholinesterase (AChE) activity in cholinergic areas. Overall, ICSS was shown to be capable of facilitating both types of memory, while the blockade of OX1R had a detrimental effect. Moreover, ICSS seems to compensate for the impairment caused by SB-334867. Furthermore, ICSS promotes flexible spatial memory, but an inflexible SVD memory. In addition, histological observations revealed that ICSS increased c-Fos expression in memory-related areas, while OX1R blockade decreased activation in most of said areas, as well as AChE levels in cholinergic regions. Finally, SB-334867 administration seemed to partially negate ICSS facilitation of the spatial memory task, while it completely negated the facilitative effect of the treatment for the SVD task in the MWM.
This dissertation sheds further light on the implication of the orexinergic system in the facilitation of memory by ICSS. More specifically, it highlights the extensive involvement of orexin-A and its selective receptor OX1R in aspects such as consolidation, long-term retention and cognitive flexibility in both implicit and explicit memory. In addition, it provides insight into the differential participation of OX1R in the reversal of each task, depending on how flexible that type of memory is. Overall, we concluded that blocking OX1R partially impedes the facilitation of memory by ICSS, but that this effect varies depending on the type of memory task and specific aspects of memory.
