Progression in Time of Dentate Gyrus Granule Cell Layer Widening due to Excitotoxicity Occurs along In Vivo LTP Reinstatement and Contextual Fear Memory Recovery.

The dentate gyrus (DG) is the gateway of sensory information arriving from the perforant pathway (PP) to the hippocampus. The adequate integration of incoming information into the DG is paramount in the execution of hippocampal-dependent cognitive functions. An abnormal DG granule cell layer (GCL) widening due to granule cell dispersion has been reported under hyperexcitation conditions in animal models as well as in patients with mesial temporal lobe epilepsy, but also in patients with no apparent relation to epilepsy. Strikingly, it is unclear whether the presence and severity of GCL widening along time affect synaptic processing arising from the PP and alter the performance in hippocampal-mediated behaviors. To evaluate the above, we injected excitotoxic kainic acid (KA) unilaterally into the DG of mice and analyzed the evolution of GCL widening at 10 and 30 days post injection (dpi), while analyzing if KA-induced GCL widening affected in vivo long-term potentiation (LTP) in the PP-DG pathway, as well as the performance in learning and memory through contextual fear conditioning. Our results show that at 10 dpi, when a subtle GCL widening was observed, LTP induction, as well as contextual fear memory, were impaired. However, at 30 dpi when a pronounced increase in GCL widening was found, LTP induction and contextual fear memory were already reestablished. These results highlight the plastic potential of the DG to recover some of its functions despite a major structural alteration such as abnormal GCL widening.

Improved post-stroke spontaneous recovery by astrocytic extracellular vesicles.

Spontaneous recovery after a stroke accounts for a significant part of the neurological recovery in patients. However limited, the spontaneous recovery is mechanistically driven by axonal restorative processes for which several molecular cues have been previously described. We report the acceleration of spontaneous recovery in a preclinical model of ischemia/reperfusion in rats via a single intracerebroventricular administration of extracellular vesicles released from primary cortical astrocytes. We used magnetic resonance imaging and confocal and multiphoton microscopy to correlate the structural remodeling of the corpus callosum and striatocortical circuits with neurological performance during 21 days. We also evaluated the functionality of the corpus callosum by repetitive recordings of compound action potentials to show that the recovery facilitated by astrocytic extracellular vesicles was both anatomical and functional. Our data provide compelling evidence that astrocytes can hasten the basal recovery that naturally occurs post-stroke through the release of cellular mediators contained in extracellular vesicles.

BDNF induces in vivo long-lasting enhancement of synaptic transmission and structural reorganization at the hippocampal mossy fibers in a transcription and translation-independent manner.

Brain-derived neurotrophic factor (BDNF) is an essential product of protein synthesis with a prominent impact on brain signaling and synaptic plasticity. Exogenous application of this neurotrophin is able to induce long-term potentiation (LTP) in several brain structures such as the hippocampus along with increases in gene transcription and translation of proteins involved in functional and structural plasticity. In this regard, our previous studies have demonstrated that acute intrahippocampal administration of BDNF induces long-lasting enhancement of synaptic transmission at the mossy fibers projection (MF) accompanied by a structural reorganization at the CA3 hippocampus area. Thus, considering the non-canonical molecular mechanisms underlying MF-CA3-LTP and the high expression of this neurotrophin in the CA3 area, we wonder whether transcriptional and translational inhibition interferes with the persistence of the MF functional and structural synaptic plasticity elicited by BDNF in adult rats in vivo. Our results show that BDNF is able to induce a lasting potentiation of synaptic efficacy at the MF projection accompanied by a structural reorganization at the CA3 area in an mRNA synthesis and protein translation-independent manner. The present findings support the idea that BDNF is an essential plasticity related product, which is necessary and sufficient to induce and maintain functional and structural synaptic plasticity at the MF-CA3 pathway.

Bidirectional modulation of taste aversion extinction by insular cortex LTP and LTD.

The history of activity of a given neuron has been proposed to bidirectionally influence its future response to synaptic inputs. In particular, induction of synaptic plasticity expressions such as long-term potentiation (LTP) and long-term depression (LTD) modifies the performance of several behavioral tasks. Our previous studies in the insular cortex (IC), a neocortical region that has been related to acquisition and retention of conditioned taste aversion (CTA), have demonstrated that induction of LTP in the basolateral amygdaloid nucleus (Bla)-IC pathway before CTA training enhances the retention of this task. In addition, we reported that CTA training triggers a persistent impairment in the ability to induce in vivo LTP in the IC. The aim of the present study was to investigate whether LTD can be induced in the Bla-IC projection in vivo, as well as, whether the extinction of CTA is bidirectionally modified by previous synaptic plasticity induction in this pathway. Thus, rats received 900 train pulses (five 250µs pulses at 250Hz) delivered at 1Hz in the Bla-IC projection in order to induce LTD or 10 trains of 100Hz/1s with an intertrain interval of 20s in order to induce LTP. Seven days after surgery, rats were trained in the CTA task including the extinction trials. Our results show that the Bla-IC pathway is able to express in vivo LTD in an N-Methyl-D-aspartate (NMDA) receptor-dependent manner. Induction of LTD in the Bla-IC projection previous to CTA training facilitates the extinction of this task. Conversely, LTP induction enhances CTA retention. The present results show the bidirectional modulation of CTA extinction in response to IC-LTP and LTD, providing evidence of the homeostatic adaptation of taste learning.

Brain-derived neurotrophic factor into adult neocortex strengthens a taste aversion memory.

Nowadays, it is known that brain derived neurotrophic-factor (BDNF) is a protein critically involved in regulating long-term memory related mechanisms. Previous studies from our group in the insular cortex (IC), a brain structure of the temporal lobe implicated in acquisition, consolidation and retention of conditioned taste aversion (CTA), demonstrated that BDNF is essential for CTA consolidation. Recent studies show that BDNF-TrkB signaling is able to mediate the enhancement of memory. However, whether BDNF into neocortex is able to enhance aversive memories remains unexplored. In the present work, we administrated BDNF in a concentration capable of inducing in vivo neocortical LTP, into the IC immediately after CTA acquisition in two different conditions: a "strong-CTA" induced by 0.2M lithium chloride i.p. as unconditioned stimulus, and a "weak-CTA" induced by 0.1M lithium chloride i.p. Our results show that infusion of BDNF into the IC converts a weak CTA into a strong one, in a TrkB receptor-dependent manner. The present data suggest that BDNF into the adult insular cortex is sufficient to increase an aversive memory-trace.

Late Protein Synthesis-Dependent Phases in CTA Long-Term Memory: BDNF Requirement.

It has been proposed that long-term memory (LTM) persistence requires a late protein synthesis-dependent phase, even many hours after memory acquisition. Brain-derived neurotrophic factor (BDNF) is an essential protein synthesis product that has emerged as one of the most potent molecular mediators for long-term synaptic plasticity. Studies in the rat hippocampus have been shown that BDNF is capable to rescue the late-phase of long-term potentiation as well as the hippocampus-related LTM when protein synthesis was inhibited. Our previous studies on the insular cortex (IC), a region of the temporal cortex implicated in the acquisition and storage of conditioned taste aversion (CTA), have demonstrated that intracortical delivery of BDNF reverses the deficit in CTA memory caused by the inhibition of IC protein synthesis due to anisomycin administration during early acquisition. In this work, we first analyze whether CTA memory storage is protein synthesis-dependent in different time windows. We observed that CTA memory become sensible to protein synthesis inhibition 5 and 7 h after acquisition. Then, we explore the effect of BDNF delivery (2 µg/2 µl per side) in the IC during those late protein synthesis-dependent phases. Our results show that BDNF reverses the CTA memory deficit produced by protein synthesis inhibition in both phases. These findings support the notion that recurrent rounds of consolidation-like events take place in the neocortex for maintenance of CTA memory trace and that BDNF is an essential component of these processes.