Molecular mechanisms of classical fear conditioning : GABAergic factors and their role in fear-related network activities

Magdeburg, Univ., Fak. für Naturwiss., Diss., 2010Jorge R. Bergado Acost

Efector del factor de crecimiento nervioso (NGF) sobre la conducta en un modelo experimental de Corea de Huntington en ratas.

Pág. 55-68La enfermedad de Huntington (EH) es un trastorno neurodegenerativo que afecta a los ganglios basales. El uso de factores neurotróficos ha sido propuesto como posible tratamiento de esta enfermedad. El objetivo de nuestro estudio fue el de evaluar los efectos del factor de crecimiento neural (NGF) en el modelo de Huntington inducido por la lesión estriatal de acido queinolínico (AQ). Para el estudio se utilizaron ratas las cuales fueron lesionadas con AQ (112mM, pH = 7,4) las cuales fueron tratadas con NG, en diferentes tiempos en relación al día de la lesión: NGF 2 días antes de la inducción de la lesión (NGFAQ), NGF simultaneo con la lesión (AQ+NGF) y NGF 2 días después de la lesión (AQNGF). Los animales intactos y lesionados sin tratamiento sirvieron como grupos controles. Se realizaron estudios conductuales para evaluar los efectos de la lesión y del tratamiento sobre la memoria y aprendizaje espacial (laberinto acuático de Morris) y la actividad motora (rotación inducida por anfetamina). Los resultados de nuestro experimento demostraron que el NGF parece actuar de forma preventiva en la neuroprotección de poblaciones neuronales en el estriado demostrado en los estudios conductuales.ABSTRACT The Huntington disease is neurodegenerative pathology with affects the basal ganglia. The neutrotrophic factors have been suggested as a possible treatment of the disease. The aims of our study were to increase our knowledge about the behavioral characterization of the Huntington models induced by quinolinic acid (QA) and the effects of nerve growth factor (NGF). In our work we used rats with unilateral lesion of striatum induced by AQ (112mM, pH=7,4), which received NGF-treatment in different times in relation to the day of the lesion: NGF 2 day before the lesion (NGFQA), NGF simultaneously with QA (QA+NGF) and NGF 2 day after the lesion (QANGF). The intact and lesioned rats without treatment served as the control groups. The memory (Morris water maze) and motor activity (rotational behavior induced by amphetamine) were evaluated to study the effects of the lesion and treatment. Our results demonstrated that this early application of NGF has like preventives action in the neuroprotection of striatal population demostrated in behavioral results

Critical role of the 65-kDa isoform of glutamic acid decarboxylase in consolidation and generalization of Pavlovian fear memory

Evidence suggests that plasticity of the amygdalar and hippocampal GABAergic system is critical for fear memory formation. In this study we investigated in wild-type and genetically manipulated mice the role of the activity-dependent 65-kDa isozyme of glutamic acid decarboxylase (GAD65) in the consolidation and generalization of conditioned fear. First, we demonstrate a transient reduction of GAD65 gene expression in the dorsal hippocampus (6 h post training) and in the basolateral complex of the amygdala (24 h post training) during distinct phases of fear memory consolidation. Second, we show that targeted ablation of the GAD65 gene in Gad65−/− mice results in a pronounced context-independent, intramodal generalization of auditory fear memory during long-term (24 h or 14 d) but not short-term (30 min) memory retrieval. The temporal specificity of both gene regulation and memory deficits in Gad65 mutant mice suggests that GAD65-mediated GABA synthesis is critical for the consolidation of stimulus-specific fear memory. This function appears to involve a modulation of neural activity patterns in the amygdalo-hippocampal pathway as indicated by a reduction in theta frequency synchronization between the amygdala and hippocampus of Gad65−/− mice during the expression of generalized fear memory

Regulation of CREB Phosphorylation in Nucleus Accumbens after Relief Conditioning

Relief learning is the association of environmental cues with the cessation of aversive events. While there is increasing knowledge about the neural circuitry mediating relief learning, the respective molecular pathways are not known. Therefore, the aim of the present study was to examine different putative molecular pathways underlying relief learning. To this purpose, male rats were subjected either to relief conditioning or to a pseudo conditioning procedure. Forty-five minutes or 6 h after conditioning, samples of five different brain regions, namely the prefrontal cortex, nucleus accumbens (NAC), dorsal striatum, dorsal hippocampus, and amygdala, were collected. Using quantitative Western blots, the expression level of CREB, pCREB, ERK1/2, pERK1/2, CaMKIIα, MAP2K, PKA, pPKA, Akt, pAkt, DARPP-32, pDARPP-32, 14-3-3, and neuroligin2 were studied. Our analyses revealed that relief conditioned rats had higher CREB phosphorylation in NAC 6 h after conditioning than pseudo conditioned rats. The data further revealed that this CREB phosphorylation was mainly induced by dopamine D1 receptor-mediated activation of PKA, however, other kinases, downstream of the NMDA receptor, may also contribute. Taken together, the present study suggests that CREB phosphorylation, induced by a combination of different molecular pathways downstream of dopamine D1 and NMDA receptors, is essential for the acquisition and consolidation of relief learning

Exploration of a novel virtual environment improves memory consolidation in ADHD

Experimental evidence in rodents and humans suggests that long-term memory consolidation can be enhanced by the exploration of a novel environment presented during a vulnerable early phase of consolidation. This memory enhancing effect (behavioral tagging) is caused by dopaminergic and noradrenergic neuromodulation of hippocampal plasticity processes. In translation from animal to human research, we investigated whether behavioral tagging with novelty can be used to tackle memory problems observed in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). 34 patients with ADHD and 34 typically developing participants (age 9–15 years) explored either a previously familiarized or a novel virtual environment 45 min after they had learned a list of 20 words. Participants took a free recall test both immediately after learning the word list and after 24 h. Patients who explored a familiar environment showed significantly impaired memory consolidation compared to typically developing peers. Exploration of a novel environment led to significantly better memory consolidation in children and adolescents with ADHD. However, we did not observe a beneficial effect of novel environment exploration in typically developing participants. Our data rather suggested that increased exploration of a novel environment as well as higher feelings of virtual immersion compromised memory performance in typically developing children and adolescents, which was not the case for patients with ADHD. We propose that behavioral tagging with novel virtual environments is a promising candidate to overcome ADHD related memory problems. Moreover, the discrepancy between children and adolescents with and without ADHD suggests that behavioral tagging might only be able to improve memory consolidation for weakly encoded information.DFG-Publikationsfonds 202

Transgenic modeling of Ndr2 gene amplification reveals disturbance of hippocampus circuitry and function

Duplications and deletions of short chromosomal fragments are increasingly recognized as the cause for rare neurodevelopmental conditions and disorders. The NDR2 gene encodes a protein kinase important for neuronal development and is part of a microduplication region on chromosome 12 that is associated with intellectual disabilities, autism, and epilepsy. We developed a conditional transgenic mouse with increased Ndr2 expression in postmigratory forebrain neurons to study the consequences of an increased gene dosage of this Hippo pathway kinase on brain circuitry and cognitive functions. Our analysis reveals reduced terminal fields and synaptic transmission of hippocampal mossy fibers, altered hippocampal network activity, and deficits in mossy fiber-dependent behaviors. Reduced doublecortin expression and protein interactome analysis indicate that transgenic Ndr2 disturbs the maturation of granule cells in the dentate gyrus. Together, our data suggest that increased expression of Ndr2 may critically contribute to the development of intellectual disabilities upon gene amplification