Distinct Contributions of Median Raphe Nucleus to ContextualFear Conditioning and Fear‐Potentiated Startle

Abstract

Ascending 5-HT projections from the median raphe nucleus (MRN), probably to the hippocampus, are implicated in the acquisition of contextual fear (background stimuli), as assessed by freezing behavior. Foreground cues like light, used as a conditioned stimulus (CS) in classical fear conditioning, also cause freezing through thalamic transmission to the amygdala. As the MRN projects to the hippocampus and amygdala, the role of this raphe nucleus in fear conditioning to explicit cues remains to be explained. Here we analyzed the behavior of rats with MRN electrolytic lesions in a contextual conditioning situation and in a fear-potentiated startle procedure. The animals received MRN electrolytic lesions either before or on the day after two consecutive training sessions in which they were submitted to 10 conditioning trials, each in an experimental chamber (same context) where they. received foot-shocks (0.6 mA, 1 sec) paired to a 4-sec light CS. Seven to ten days later, the animals were submitted to testing sessions for assessing conditioned fear when they were placed for five shocks, and the duration of contextual freezing was recorded. The animals were then submitted to a fear-potentiated startle in response to a 4-sec light-CS, followed by white noise (100 dB, 50 ms). Control rats (sham) tested in the same context showed more freezing than did rats with pre- or post-training MRN lesions. Startle was clearly potentiated in the presence of light CS in the sham-lesioned animals. Whereas pretraining lesions reduced both freezing and fear-potentiated startle, the post-training lesions reduced only freezing to context, without changing the fear-potentiated startle. In a second experiment, neurotoxic lesions of the MRN with local injections of N-methyl-D-aspartate or the activation of 5-HT1A somatodendritic auto-receptors of the MRN by microinjections of the 5-HT1A receptor agonist 8-hydroxy- 2-(di-n-propylamino)tetralin (8-OH-DPAT) before the training sessions also reduced the amount of freezing and the fear-potentiated startle. Freezing is a prominent response of contextual fear conditioning, but does not seem to be crucial for the enhancement of the startle reflex by explicit aversive cues. As fear-potentiated startle may be produced in posttraining lesioned rats that are unable to freeze to fear contextual stimuli, dissociable systems seem to be recruited in each condition. Thus, contextual fear and fear-potentiated startle are conveyed by distinct 5-HT-mediated circuits of the MRN.

Metaplastic Regulation of the Median Raphe Nucleus via Serotonin 5-HT1A Receptor on Hippocampal Synaptic Plasticity Is Associated With Gender-Specific Emotional Expression in Rats

“…Considering the similarity of synaptic changes, these results strongly suggest that 5-HTergic function in the MRN-hippocampus pathway is involved in gender differences in response to fear stress. These findings were supported by the results observed in lesion studies in the males; freezing expression during exposure to CFC was reduced by electrical lesion of the MRN, as reported in the males with neurotoxic lesions of the MRN (47). Reduction of freezing in the MRN-lesioned males is similar to the CFC-induced behavioral pattern in the females.…”

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

“…There is further topographical organization within the DRN itself. Although the possible significance of this organization will not be discussed here, Lowry and colleagues among others have shown that certain DRN subregions appear to be preferentially involved in stress and anxiety (Abrams et al, 2004(Abrams et al, , 2005Lowry, 2002;Maier and Watkins, 2005;Silva et al, 2002).…”

Mediação do medo condicionado contextual por mecanismos serotoninérgicos do circuito núcleo mediano da rafe-hipocampo dorsal

“…A amígdala, o hipocampo e o núcleo mediano da rafe estão criticamente envolvidos na regulação das respostas de medo condicionado contextual (MCNISH, 1997;AVANZI;BRANDÃO, 2003;BRANDÃO, 2004).…”

“…Desta forma, as projeções serotoninérgicas que saem do NMR, principal fonte de transmissão serotoninérgica no encéfalo, em direção à amígdala e ao septo-hipocampo são de grande importância na modulação do medo contextual (AZMITIA; SEGAL, 1978;GRAY;MCNAUGHTON, 2000;SILVA et al, 2002).…”

“…O hipocampo estabelece diversas conexões com estruturas encefálicas, o que lhe confere um papel importante na transmissão dos mais complexos sinais envolvidos no processamento das informações aversivas. Nesse sentido, as projeções hipocampais para a amígdala desatacam-se nessa circuitaria (LEDOUX et al, 1987 A principal fonte de neurônios serotoninérgicos no mesencéfalo, o NMR envia projeções para amígdala, septo e hipocampo (AZMITIA; SEGAL, 1978;GRAY;MCNAUGHTON, 2000;SILVA et al, 2002). As principais conexões serotoninérgicas estão ilustradas na Figura 1.…”