The neuropeptide‐12 improves recognition memory and neuronal plasticity of the limbic system in old rats

Abstract

Aging is a stage of life where cognitive and motor functions are impaired. This is because oxidative and inflammatory processes exacerbate neurodegeneration, which affects dendritic morphology and neuronal communication of limbic regions with memory loss. Recently, the use of trophic substances has been proposed to prevent neuronal deterioration. The neuropeptide-12 (N-PEP-12) has been evaluated in elderly patients with dementia, showing improvements in cognitive tasks due to acts as a neurotrophic factor. In the present work, we evaluated the effect of N-PEP-12 on motor activity and recognition memory, as well as its effects on dendritic morphology and the immunoreactivity of GFAP, Synaptophysin (SYP), and BDNF in neurons of the prefrontal cortex (PFC), dorsal hippocampus (DH) and nucleus accumbens (NAcc) of aged rats. The results show that N-PEP-12 improved the recognition memory, but the motor activity was not modified compared to the control animals. N-PEP-12 increases the density of dendritic spines and the total dendritic length in neurons of the PFC (layers 3 and 5) and in DH (CA1 and CA3). Interestingly NAcc neurons showed a reduction in the number of dendritic spines. In the N-PEP-12 animals, when evaluating the immunoreactivity for SYP and BDNF, there was an increase in the three brain regions, while the mark for GFAP decreased significantly. Our results suggest that N-PEP-12 promotes neuronal plasticity in the limbic system of aged animals, which contributes to improving recognition memory. In this sense, N-PEP-12 can be considered as a pharmacological alternative to prevent or delay brain aging and control senile dementias.

Pregnancies alters spine number in cortical and subcortical limbic brain regions of old rats

“…According to the current data, several reports showed that aging caused a reduction in physical activity, including locomotor activity in a novel environment in rodents and humans (Ayers & Verghese, ; Ingram & Jucker, ; Lafoux, Baudry, Bonhomme, Ruyet, & Huchet, ; Yu, Xu, Song, Ji, & Zhang, ). Additionally, some reports have suggested a reduction in spinogenesis and in dendritic length in aged animals (Alcántara‐González et al, , ; Cabrera‐Pedraza et al, ; Diaz et al, ; Hernández‐Hernández et al, ; Juárez et al, ; Sánchez et al, ; Solis‐Gaspar, Vazquez‐Roque, Jesús Gómez‐Villalobos, & Flores, ; Vidal et al, ; Xu et al, ). Furthermore, a recent report about an animal model with premature aging, the spontaneous hypertensive rat, suggests that the structure that is first affected is layer 3 of the PFC, the NAcc, and later the CA1 of the dorsal hippocampus (Sánchez et al, ).…”

“…Finally, it is important to clarify that most of these reports involve male animals (Alcántara‐González et al, ; ; Diaz et al, 2017; Hernández‐Hernández et al, ; Juárez et al, ; Vidal et al, ; Xu et al, ). Consequently, it is essential to carry out more research in female organisms about the exact role of aging on dendritic morphology.…”

“…In addition, the PFC and CA1 of the hippocampus also send glutamatergic projections to the MSN of the NAcc, the main structure in reward processes such as social rewards (Dölen, Darvishzadeh, Huang, & Malenka, ). In addition, the learning and memory processes are reduced in aging animals (Cabrera‐Pedraza et al, ; Duarte‐Guterman, Yagi, Chow, & Galea, ; Flores, ; Haam & Yakel, ; Hernández‐Hernández et al, ; Solis‐Gaspar et al, ; Vidal et al, ) and are correlated with several processes including reduced spinogenesis and shrinkage of the dendritic arbor. However, our results suggest that animals with two and three pregnancies had a higher number of dendritic spines in PFC layers 3 and 5, and rats with two pregnancies also showed a greater number of dendritic spines in the CA1 region of the dorsal hippocampus.…”

“…Each neuron reconstruction was done using the Sholl analysis (Flores et al, ; Sholl, ). In brief, with the help of transparent grid with equidistant concentric rings, total dendritic length, arborization, and length per branch order were assessed (Flores et al, , ; Hernández‐Hernández et al, ). Finally, we estimated the number of dendritic spines by drawing a long segment from the terminal tips (at least 10 µm) at high magnification (1,000×).…”

Consequences of diabetes mellitus on neuronal connectivity in limbic regions

“…However, how high glucose levels are able to damage the dendritic tree and reduce spinogenesis in limbic regions such as the PFC and the hippocampus at this moment is not clear. However, dendritic trees and dendritic spine density are regulated by several factors which include: neurotrophins such as brain‐derived neurotrophic factor (BDNF), hormones such as estrogens or growth hormone, neurotransmitters such as glutamate or dopamine, channels such as small‐conductance Ca 2+ ‐activated K + channel, biomolecules such as NO, etc., (Arroyo‐García et al, ; Bringas et al, ; Diaz et al, ; Flores et al, ; Hernández‐Hernández et al, ; Morales‐Medina et al, ; Olivares‐Hernández et al, ; Romero‐Curiel et al, ; Shira et al, ; Woolley & McEwen, ). For example, recent reports suggest that hyperglycemia, in patients with type 2 diabetes and in the Streptozotocin animal model, reduce BDNF levels in the serum and hippocampus (Bathina et al, ; Calleti et al, ; Krabbe et al, ; Zhen et al, ).…”