Purpose: To investigate a possible role of neurotrophins in the memory improving effect of stimulating the basolateral amygdala. Methods: The BDNF and NGF levels were measured in the hippocampus of fimbria-fornix lesioned male rats after four days of training in the water maze and stimulation of the basolateral amygdala. Results: The behavioral results confirm that daily post-training stimulation of the amygdala improves the learning abilities of the lesioned animals. BDNF increased in lesioned and trained animals, but stimulating the basolateral amygdala induces a significantly greater increase. NGF showed a slight (but significant) increase in fimbria-fornix lesioned and trained animals, but stimulating the amygdala does not produce a further increase. In separate groups of animals we measured the levels of both neurotrophins in acute experiments, after 2 and 24 hours of stimulating the amygdala. BDNF was significantly increased at both times, while NGF showed again only slight increases (significant at 24 h). Conclusions: These results suggest that the BDNF response to amygdala stimulation might be of functional importance in the observed learning improvement. The changes in NGF are most likely due to the accumulation of this protein after removal of the septal axons.

Erythropoietin (EPO), the master regulator of erythropoiesis, is emerging as a pivotal mediator of brain repair. While its capacity to mitigate neural damage is well-documented, we posit that its most profound potential lies in actively orchestrating functional restoration. In the present review we summarize the molecular biology of EPO and the evidence establishing EPO as a potent modulator of neuroplasticity. We use an experimental strategy in which a specific behavioral task marks experience-activated neural circuits, and a subsequent, temporally precise administration of EPO provides a surge of plasticity-related proteins. This creates a synergistic interaction where the proteins are selectively captured by the activated synapses, directing plastic changes with high specificity. We present experimental evidence demonstrating that this synchronized protocol enables the recovery of spatial memory, reinstates synaptic plasticity, and activates genetic programs for plasticity in rodent models of brain injury. Furthermore, we show that endogenous EPO signaling is itself activity-dependent and integral to memory formation. This redefines EPO as a precision tool for neurorestoration, a potential now being pursued with engineered, non-erythropoietic variants of EPO in clinical trials for neurological and psychiatric disorders.

Although many studies have addressed the role of the amygdala in modulating long-term memory, it is not known whether weak training plus amygdala stimulation can transform a short-term memory into a remote memory. Object place recognition (OPR) memory after strong training remains hippocampus-dependent through the persistent action of PKMζ for at least 6 days, but it is unknown whether weak training plus amygdala stimulation can transform short-term memory into an even longer memory, and whether such memory is stored through more persistent action of PKMζ in hippocampus. We trained rats to acquire OPR and 15 min or 5 h later induced a brief pattern of electrical stimulation in basolateral amygdala (BLA). Our results reveal that a short-term memory lasting < 4 h can be converted into remote memory lasting at least 3 weeks if the BLA is activated 15 min, but not 5 h after learning. To examine how this remote memory is maintained, we injected ZIP, an inhibitor of atypical PKCs (aPKCs), PKMζ and PKCι/λ, into either hippocampal CA1, dentate gyrus (DG), or anterior cingulate cortex (ACC). Our data reveal amygdala stimulation produces consolidation into remote memory, not by persistent aPKC activation and capture by synaptic tagging processes in the hippocampal formation, but in ACC. Our data establish a powerful modulating role of the BLA in forming remote memory and open a path in the search for neurological restoration of memory, based on enhancing synaptic plasticity in aging or neurodegenerative disorders such as Alzheimer’s disease.

Background: Alzheimer´s disease is the most common disease in the worldwide and despite the great efforts made at present cure is lacking. In this work we study whether the basolateral region of the amygdala (BLA) stimulation, a brain region known as for its role in emotions and motivations, memory and learning formation, and which is capable of broadly promoting neural plasticity mechanisms, is capable of promote the recovery of spatial memory in the genetic model of Alzheimer's disease known as 5XFAD. Method: To test this hypothesis, we used 12‐13‐month‐old mice 5XFAD. A bipolar stimulation electrode was attached bilaterally in the BLA through stereotactic surgery and 15 min after behavioral training the BLA was stimulated consisted in 3 trains of 15 pulses at 200 Hz. A week later the animals were trained in the Morris Water Maze (MWM) for 5 days and 15 min after the end tasks BLA was stimulated. Additionally, in order to evaluate if this proceeding produces a general memory recovery we evaluated the animals in other two behavioral tasks, Novel Object Recognition Test (NORT) and Place Recognition Test (PRT). Finally, we search if the combination of MWM plus 15 min after BLA stimulation improved Long‐Term Synaptic Potentiation (LTP), cellular model for learning and memory, which is affected in 5XFAD. Result: We showed that MWM plus 15 min after BLA stimulation treatment for four days produced a memory recovery in 5XFAD mice, and more important in NORT and PRT too, suggesting is not just facilitation of particular memory trace if not a general recovery of skill learning and memory. Furthermore, MWM plus BLA stimulation treatment also produced an improvement in LTP, especially in its maintenance, since LTP in 5XFAD mice decay rapidly. Conclusion: Combination MWM plus BLA stimulation is able to induce plasticity related mechanisms involved in learning and memory but also in functional recovery, which produces skill‐memory recovery in the 5XFAD mice. This result opens a path in the search for neurological restoration based on the plasticity of memory loss in Alzheimer's disease.

Erythropoietin (EPO), the master regulator of erythropoiesis, is emerging as a pivotal mediator of brain repair. While its capacity to mitigate neural damage is well-documented, we posit that its most profound potential lies in actively orchestrating functional restoration. In the present review we summarize the molecular biology of EPO and the evidence establishing EPO as a potent modulator of neuroplasticity. We use an experimental strategy in which a specific behavioral task marks experience-activated neural circuits, and a subsequent, temporally precise administration of EPO provides a surge of plasticity-related proteins. This creates a synergistic interaction where the proteins are selectively captured by the activated synapses, directing plastic changes with high specificity. We present experimental evidence demonstrating that this synchronized protocol enables the recovery of spatial memory, reinstates synaptic plasticity, and activates genetic programs for plasticity in rodent models of brain injury. Furthermore, we show that endogenous EPO signaling is itself activity-dependent and integral to memory formation. This redefines EPO as a precision tool for neurorestoration, a potential now being pursued with engineered, non-erythropoietic variants of EPO in clinical trials for neurological and psychiatric disorders