Serotonergic mechanisms of the median raphe nucleus–dorsal hippocampus in conditioned fear: Output circuit involves the prefrontal cortex and amygdala

Almada, Rafael Carvalho; Borelli, Karina Genaro; Albrechet‐Souza, Lucas; Brandão, Marcus Lira

doi:10.1016/j.bbr.2009.05.017

Cited by 50 publications

(52 citation statements)

References 57 publications

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“…The rodent mPFC projects extensively to the NAc and receives projections from many cortical and subcortical areas including the hippocampal formation (Almada et al 2009;Hoover and Vertes 2007;Tanji and Hoshi 2008;Tzschentke and Schmidt 2000). We therefore assessed delayed alternation performance after mPFC, dorsal hippocampus, and NAc lesions.…”

Section: Excitotoxic Lesionsmentioning

confidence: 99%

“…Damage to the PFC commonly produced impairments in so-called working memory, the capacity to hold relevant information online in coordinating goal-directed behavior (Fuster 2001;Miller and Cohen 2001). Previous work has also implicated the nucleus accumbens (NAc) and hippocampus, areas functionally and anatomically connected with medial (m)PFC (Almada et al 2009;Hoover and Vertes 2007), in spatial working memory (Klein et al 2004;Murray et al 2011).…”

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confidence: 99%

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Prefrontal cortical mechanisms underlying delayed alternation in mice

Rossi

Hayrapetyan

Maimon

et al. 2012

Journal of Neurophysiology

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HH. Prefrontal cortical mechanisms underlying delayed alternation in mice. J Neurophysiol 108: 1211-1222, 2012. First published April 25, 2012 doi:10.1152/jn.01060.2011The prefrontal cortex (PFC) has been implicated in the maintenance of task-relevant information during goal-directed behavior. Using a combination of lesions, local inactivation, and optogenetics, we investigated the functional role of the medial prefrontal cortex (mPFC) in mice with a novel operant delayed alternation task. Task difficulty was manipulated by changing the duration of the delay between two sequential actions. In experiment 1, we showed that excitotoxic lesions of the mPFC impaired acquisition of delayed alternation with long delays (16 s), whereas lesions of the dorsal hippocampus and ventral striatum, areas connected with the PFC, did not produce any deficits. Lesions of dorsal hippocampus, however, significantly impaired reversal learning when the rule was changed from alternation to repetition. In experiment 2, we showed that local infusions of muscimol (an agonist of the GABA A receptor) into mPFC impaired performance even when the animal was well trained, suggesting that the mPFC is critical not only for acquisition but also for successful performance. In experiment 3, to examine the mechanisms underlying the role of GABAergic inhibition, we used Cre-inducible Channelrhodopsin-2 to activate parvalbumin (PV)-expressing GABAergic interneurons in the mPFC of PV-Cre transgenic mice as they performed the task. Using whole cell patch-clamp recording, we demonstrated that activation of PV-expressing interneurons in vitro with blue light in brain slices reliably produced spiking and inhibited nearby pyramidal projection neurons. With similar stimulation parameters, in vivo stimulation significantly impaired delayed alternation performance. Together these results demonstrate a critical role for the mPFC in the acquisition and performance of the delayed alternation task. channelrhodopsin; interneuron; operant; optogenetics; parvalbumin THE PREFRONTAL CORTEX (PFC) is widely thought to be involved in higher cognitive functions, as shown by studies in primates (Castner et al.

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Section: Excitotoxic Lesionsmentioning

confidence: 99%

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confidence: 99%

Prefrontal cortical mechanisms underlying delayed alternation in mice

Rossi

Hayrapetyan

Maimon

et al. 2012

Journal of Neurophysiology

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“…Indeed, endogenous 5-HT inhibits the firing activity of hippocampal CA1 pyramidal neurons through 5-HT 1A receptors (Tada et al, 2004), and activation of the 5-HT 1A receptors in the DH decreases the expression of CFC (Almada et al, 2009). Therefore, our results are in line with the evidence that was discussed earlier and suggest that mirtazapine activates the MRN-to-DH 5-HT 1A pathway and inhibits DH neurons that are necessary for constructing and retrieving fear-related contextual information.…”

Section: Discussionmentioning

confidence: 99%

Mirtazapine exerts an anxiolytic-like effect through activation of the median raphe nucleus-dorsal hippocampal 5-HT pathway in contextual fear conditioning in rats

Chen

Inoue

et al. 2016

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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“…Recent evidence suggests that 5-HT neurons within the MRN play an important role in the regulation of anxiety-related behaviors in several animal models such as the social interaction test, elevated plus-maze test, light-dark transition test, elevated T-maze test and the conditioned fear test (Almada et al, 2009;File et al, 1996;Vicente et al, 2008). The great density of α 1 -and α 2 -adrenoceptors in the MRN shown by anatomical studies (Day et al, 1997;Rosin et al, 1993;Talley et al, 1996) reportedly modulates the firing of MRN serotonergic neurons: α 1 -adrenoceptors directly stimulate serotonergic neuron firing and α 2 -adrenoceptors indirectly inhibit it through the inhibition of noradrenergic neurons (Adell and Artigas, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the median raphe nucleus (MRN) also has an important role in the acquisition and expression of conditioned fear (Almada et al, 2009;Avanzi et al, 2003;Borelli et al, 2005). Lesions or inactivation of the MRN were shown to reduce the expression of contextual fear conditioning (Borelli et al, 2005;Silva et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Anxiolytic-like effect of mirtazapine mediates its effect in the median raphe nucleus

Inoue

Kitaichi

et al. 2013

European Journal of Pharmacology

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Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), blocks the α 2 -adrenergic autoreceptors and heteroreceptors, which are responsible for controlling noradrenaline and 5-hydroxytryptamine (5-HT) release. Though preclinical and clinical studies have shown that mirtazapine exerts an anxiolytic action, its precise brain target sites remain unclear. In the present study, we investigated the brain area(s) in which mirtazapine exerts its anxiolytic-like effects on the expression of contextual conditioned freezing in rats. Mirtazapine (3 μg/site) was directly injected into three brain structures, the median raphe nucleus (MRN), hippocampus and amygdala. Freezing behavior tests were carried out 10 min after injections. Our results showed that the intra-MRN injection of mirtazapine reduced freezing significantly, whereas injections into the hippocampus or the amygdala did not. In addition, the intra-MRN injection of mirtazapine did not affect locomotor activity.These results suggest that the anxiolytic-like effect of mirtazapine might be mediated by its action on the MRN.

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Serotonergic mechanisms of the median raphe nucleus–dorsal hippocampus in conditioned fear: Output circuit involves the prefrontal cortex and amygdala

Cited by 50 publications

References 57 publications

Prefrontal cortical mechanisms underlying delayed alternation in mice

Prefrontal cortical mechanisms underlying delayed alternation in mice

Mirtazapine exerts an anxiolytic-like effect through activation of the median raphe nucleus-dorsal hippocampal 5-HT pathway in contextual fear conditioning in rats

Anxiolytic-like effect of mirtazapine mediates its effect in the median raphe nucleus

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