ABSTRACT
The mammalian central nervous system (CNS) is considered an immune privileged system as it is separated from the periphery by the blood brain barrier (BBB). Yet, immune functions have been postulated to heavily influence the functional state of the CNS, especially after injury or during neurodegeneration. There is controversy regarding whether adaptive immune responses are beneficial or detrimental to CNS injury repair. In this study, we utilized immunocompromised SCID mice and subjected them to spinal cord injury (SCI). We analyzed motor function, electrophysiology, histochemistry, and performed unbiased RNA-sequencing. SCID mice displayed improved CNS functional recovery compared to WT mice after SCI. Weighted gene-coexpression network analysis (WGCNA) of spinal cord transcriptomes revealed that SCID mice had reduced expression of immune function-related genes and heightened expression of neural transmission-related genes after SCI, which was confirmed by immunohistochemical analysis and was consistent with better functional recovery. Transcriptomic analyses also indicated heightened expression of neurotransmission-related genes before injury in SCID mice, suggesting that a steady state of immune-deficiency potentially led to CNS hyper-connectivity. Consequently, SCID mice without injury demonstrated worse performance in Morris water maze test. Taken together, not only reduced inflammation after injury but also dampened steady-state immune function without injury heightened the neurotransmission program, resulting in better or worse behavioral outcomes respectively. This study revealed the intricate relationship between immune and nervous systems, raising the possibility for therapeutic manipulation of neural function via immune modulation.
ABSTRACT
La exposición a estímulos novedosos es un protocolo simple de emplear que involucra múltiples sistemas y procesos de memoria tales como codificación, consolidación y recuperación de la información. Esto hace plausible de emplearlo como un tratamiento útil para estudiar los mecanismos comportamentales, fisiológicos y moleculares implicados en esta función cognitiva. Se presentan estudios en modelos animales que dan cuenta de cómo la exploración de un ambiente novedoso puede ser útil para mejorar o deteriorar la memoria, en diferentes períodos ontogenéticos. Además, se presentan investigaciones que demuestran la participación de los diversos sistemas de neurotransmisión en este fenómeno así como los mecanismos moleculares implicados en este tipo de tratamiento. De este modo este tipo de tratamiento, no invasivo y sencillo de aplicar, adquiere relevancia para la ciencia aplicada como una posible alternativa para el desarrollo de estrategias de intervención en la temática.
Exposure to novel stimuli is a simple procedure to use that involved several systems and memory processes, such as acquisition, consolidation and recall of the information. Which make it a possible treatment to study the behavioral, physiological and molecular mechanism involved in this cognitive function. Novelty detection plays an important role in adaptation to the environmental changes and in the avoidance of possible dangerous. A novel stimulus elicits a response that will produce habituation when it becomes familiar. When animals are first exposed to a novel environment they explore it actively and in parallel they compare it to previous experiences, stored in its memory to evaluate the degree of novelty. On one side, it includes the response to novelty, activation, and stress-related factors and on the other hand, a response that decreases as the environment becomes familiar, which requires different processes related to learning, recall and recognition. Also, multiple studies showed that animals prefer to explore novel objects, compared with those with whom they had previous experience. Moreover, it has been shown that the ability to respond to novel stimuli is related to self-administration of various drugs, the discovery of spontaneous tumors, and even life expectancy since it was found that neophobic animals die younger than their counterpart's neophilic. In this work we presented studies that indicated how the exploration of a novel environment could be a useful tool to enhanced or deteriorated memory in different ontogenetic stages. The modulation of memory depends on the different characteristic of the treatment presentation. It was reported that the novelty presented prior to an acquisition of some training task can generate an improvement in memory performance. Although, it was founded that the novelty exploration produce an amnesic effect if it was presented after learning, showing the opposite effect. This have been shown in different paradigms such us consummatory successive negative contrast (cSNC) paradigm and inhibition avoidance, in different phases of the training. It was also important to note that this phenomenon involves different time window parameters, for example it is required that the novelty were presented at least one hour before the learning. Furthermore we mentioned data that shows that exposure to novelty during infancy induces a lasting effect of improved cognition and long-term memory that persists even in adulthood. The study of the effect of novelty in the postnatal period and its subsequent influence on other periods opens the possibility of the creative developing of strategies to improve learning and memory processes throughout the subject's life. Besides, we presented research that exhibited the implication of several neurotransmitter systems in this phenomenon and the molecular mechanisms involved in this treatment. Practically all the principal neurotransmitter systems, such as cholinergic, glutamatergic, adrenergic, among others, are involved. A lot of studies indicate that cholinergic neurotransmission plays a critical role in the processes of attention, learning and memory. The same functions correspond to the adrenergic system. The gabaergic system is also involved in the perception of novel stimuli. Glutamate receptors play an important role in the memory processes mainly. In addition, a vast number of studies also reported that the molecular brain activation is very extensive in all the process of explore a novel environment, realizing the complexity of this mechanism. Thus, this type of treatment, non-invasive and easy to apply, becomes relevant for applied science as a possible alternative for the development of many intervention strategies in the topic. Also the study of this phenomenon in post -natal period, allows thinking about possible strategies applicable in the development of this cognitive function.
ABSTRACT
Dentro de los trastornos del estado de ánimo, los trastornos depresivos son padecimientos generalmente recurrentes que tienen, según las estadísticas, una prevalencia anual de un 3 % a un 6 % en la población. Desde la década de los 60' la hipótesis aminérgica de Schildkraut y posteriores, establecieron que las depresiones estaban vinculadas a alteraciones en la neurotransmisión catecolaminérgica y serotoninérgica. Los fármacos antidepresivos apuntaron a esas disfunciones pero las dificultades terapéuticas, retraso en el inicio de la acción y limitaciones en la eficacia, llevaron a la búsqueda de otras posibilidades, que surgieron de las investigaciones sobre la neurotransmisión glutamatérgica. En modelos animales se descubrió en los comienzos de los 90' la acción antidepresiva de los fármacos que antagonizaban la neurotransmisión de los receptores N-metil-D-aspartato (NMDA). El objetivo de este trabajo se orienta a establecer los fundamentos de la teoría glutamatérgica de las depresiones y a describir los fármacos que potencialmente podrían utilizarse en la clínica...
Depressive disorders are usually recurrent diseases that, according to statistics, afects from 3 % to 6 % of the population. Since the early '60s the Schildkraut aminergic hypothesis and subsequent, established that depressions were associated with alterations in cahtecolaminegic and serotonergic neurotransmission. Antidepressant drugs aimed at these dysfunctions but the therapeutic difficulties, delayed onset of action and efficacy limitations, led to the search of other possibilities that emerged from the research on glutamatergic neurotransmission. In animal models it was discovered in the early 90's the antidepressant action of drugs antagonized the NMDA receptor neurotransmission. The objective of this work is aimed at establishing the foundations of the glutamatergic theory of depressions and describe drugs that potentially could be used in the clinic...