Temporal lobe epilepsy (TLE) is a devastating disease in which aberrant synaptic plasticity plays a major role. We identify matrix metalloproteinase (MMP) 9 as a novel synaptic enzyme and a key pathogenic factor in two animal models of TLE: kainate-evoked epilepsy and pentylenetetrazole (PTZ) kindling–induced epilepsy. Notably, we show that the sensitivity to PTZ epileptogenesis is decreased in MMP-9 knockout mice but is increased in a novel line of transgenic rats overexpressing MMP-9. Immunoelectron microscopy reveals that MMP-9 associates with hippocampal dendritic spines bearing asymmetrical (excitatory) synapses, where both the MMP-9 protein levels and enzymatic activity become strongly increased upon seizures. Further, we find that MMP-9 deficiency diminishes seizure-evoked pruning of dendritic spines and decreases aberrant synaptogenesis after mossy fiber sprouting. The latter observation provides a possible mechanistic basis for the effect of MMP-9 on epileptogenesis. Our work suggests that a synaptic pool of MMP-9 is critical for the sequence of events that underlie the development of seizures in animal models of TLE.

Emotional states displayed by an animal or a human can seriously affect behavior of their conspecifics. The amygdala plays a crucial role in the processing of emotions. In this study, we describe an experimental rat model of between-subject transfer of emotional information and its effects on activation of the amygdala. The rats were kept in pairs, and one animal (designated as ''demonstrator'') was treated to specific behavioral training of either foot-shockreinforced context conditioning or just exposure to a novel context. We next examined the influence of the demonstrators on the exploratory behavior of their cagemates (called ''observers'') and the observers' performance of the acoustic startle response. We report that we can distinguish both groups of observers from the control animals (as shown by startle-response measure) and distinguish between observers (by means of indexing the exploration), with respect to whether they were paired with demonstrators treated to different experimental conditions. Furthermore, we show that the observers have most of their amygdala activated (as revealed by c-Fos mapping) to the same level as the demonstrators and, in the case of the central amygdala, to an even higher level. Moreover, the level of c-Fos expression in the observers reflected the specific behavioral treatment of the demonstrators with whom they were paired. Thus, in this study, we have shown that undefined emotional information transferred by a cohabitant rat can be evaluated and measured and that it evokes very strong and information-specific activation of the amygdala.c-Fos ͉ emotion ͉ social communication ͉ brain mapping ͉ empathy E motions coordinate homeostasis of an organism in a complex, dynamic environment and participate in regulation of social behaviors. Emotional states displayed by an animal or a human can seriously affect the behavior of conspecifics. This fact has been demonstrated in numerous studies involving simulated and real panic situations, in which the presence of a leader determines the time of achieving the goal of a safe exit (1, 2). The escape panic could happen in life-threatening situations, such as fires in crowded buildings, but sometimes, interestingly, it seems to emerge without any apparent cause. This kind of panic is probably provoked by the specific emotional behavior of some members of the crowd.It is well known that the elaborate emotional systems of social species, such as humans, allow the recognition of very subtle emotional signals. Most of the functional imaging studies in humans have used emotional facial expressions as social signals presented to a subject to associate differences in the social content of stimuli with differences in the activity of the neural structures engaged in the processing of such stimuli (3). The results of these studies clearly pointed to the amygdala being involved in the processing of negatively valenced stimuli of biological importance (4-6). The neuroimaging studies also revealed that fearful faces are especially effective in activa...

Understanding the function of the distinct amygdaloid nuclei in learning comprises a major challenge. In the two studies described herein, we used c-Fos immunolabeling to compare the engagement of various nuclei of the amygdala in appetitive and aversive instrumental training procedures. In the first experiment, rats that had already acquired a bar-pressing response to a partial food reinforcement were further trained to learn that an acoustic stimulus signaled either continuous food reinforcement (appetitive training) or a footshock (aversive training). The first training session of the presentation of the acoustic stimulus resulted in significant increases of c-Fos immunolabeling throughout the amygdala; however, the pattern of activation of the nuclei of the amygdala differed according to the valence of motivation. The medial part of the central amygdala (CE) responded, surprisingly, to the appetitive conditioning selectively. The second experiment was designed to extend the aversive versus appetitive conditioning to mice, trained either for place preference or place avoidance in an automated learning system (INTELLICAGE). Again, much more intense c-Fos expression was observed in the medial part of the CE after the appetitive training as compared to the aversive training. These data, obtained in two species and by means of novel experimental approaches balancing appetitive versus aversive conditioning, support the hypothesis that the central nucleus of the amygdala is particularly involved in appetitively motivated learning processes.

Background: Matrix metalloproteinase 9 is involved in fear-associated memory formation wherein transcriptional regulation is poorly known. Results: Overexpression and promoter binding activity of AP-1 factors regulate MMP-9 transcription, preceding elevated enzymatic activity in mouse brain. Conclusion: c-Fos and c-Jun AP-1 components positively regulate MMP-9 transcription in fear learning. Significance: The novel tools and approaches in vivo allowed us to explore MMP-9 transcription in mouse brain.

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Rats were subjected to two aversive learning protocols: either classical (fear conditioning) or instrumental (two-way active avoidance training). Next, immunocytochemical mapping of phosphorylated extracellular signal-regulated kinase (P-ERK) and c-Fos transcription factor protein was performed, and the expression pattern of both markers within the dorsal nucleus of lateral amygdala (LaD) was analyzed. As immunocytochemical studies revealed, aversive training induced ERK phosphorylation and c-Fos expression specifically in ventral but not dorsal tip of LaD. These data show for the first time molecular distinction between subdivisions of LaD as well as they also strengthen the idea of Repa that the neurons in the ventral tip of LaD are involved in storage of long-lasting changes associated with formation of fear memories.

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Although much has been learned about the role of the amygdala in Pavlovian fear conditioning, relatively little is known about an involvement of this structure in more complex aversive learning, such as acquisition of an active avoidance reaction. In the present study, rats with a pretraining injection of the N-methyl-D-aspartate (NMDA) receptor antagonist, 2-amino-5-phosphonopentanoic acid (APV), into the basolateral amygdala (BLA) were found to be impaired in two-way active avoidance learning. During multitrial training in a shuttle box, the APV-injected rats were not different from the controls in sensitivity to shock or in acquisition of freezing to contextual cues. However, APV injection led to impaired retention of contextual fear when tested 48 h later, along with an attenuation of c-Fos expression in the amygdala. These results are consistent with the role of NMDA receptors of the BLA in long-term memory of fear, previously documented in Pavlovian conditioning paradigms. The APV-induced impairment in the active avoidance learning coincided with deficits in directionality of the escape reaction and in attention to conditioned stimuli. These data indicate that normal functioning of NMDA receptors in the basolateral amygdala is required during acquisition of adaptive instrumental responses in a shuttle box but is not necessary for acquisition of short-term contextual fear in this situation.Pavlovian fear conditioning has become a widely used model system to study neural substrates underlying aversive learning (LeDoux 1998;Fanselow and LeDoux 1999). Using this approach, a considerable body of data has been accumulated that indicates the essential role of the nuclei of the amygdala, especially the lateral and basolateral nuclei, in associative changes during fear conditioning (Quirk et al. 1995;Maren and Fanselow 1996;Maren et al. 1996a;Schafe et al. 2000). However, the data based on inhibitory avoidance learning support the argument that the amygdala mainly modulates the consolidation of fear memories in other brain structures (McGaugh et al. 1995;Roozendaal et al. 1997;Cahill and McGaugh 1998). One of the possible resolutions of this dispute is that the amygdala may play a dual role in these paradigms; namely, that in classical fear conditioning, the amygdala serves as the site of plasticity underlying fear learning, whereas in inhibitory avoidance learning, the amygdala modulates the strength of aversive memory located elsewhere (Wilensky et al. 2000).Notably, both the fear conditioning and the inhibitory avoidance paradigms consist of a very low number of trials, thus limiting an opportunity to assess the role of the amygdala in a complex relation between fear processing and an acquisition of the instrumental reaction. One of the approaches to address this question involves more complex models of aversive learning, such as the active avoidance paradigm, which includes fear conditioning and demands dozens of trials to learn the instrumental response (for review, see Bolles 1979; Mineka 1979).The process of...