Abstract
The median raphe region (MRR) is believed to control the fear circuitry indirectly, by influencing the encoding and retrieval of fear memories by amygdala, hippocampus and prefrontal cortex. Here we show that in addition to this established role, MRR stimulation may alone elicit the emergence of remote but not recent fear memories. We substituted electric shocks with optic stimulation of MRR in C57BL/6N male mice in an optogenetic conditioning paradigm and found that stimulations produced agitation, but not fear, during the conditioning trial. Contextual fear, reflected by freezing was not present the next day, but appeared after a 7 days incubation. The optogenetic silencing of MRR during electric shocks ameliorated conditioned fear also seven, but not one day after conditioning. The optogenetic stimulation patterns (50Hz theta burst and 20Hz) used in our tests elicited serotonin release in vitro and lead to activation primarily in the periaqueductal gray examined by c-Fos immunohistochemistry. Earlier studies demonstrated that fear can be induced acutely by stimulation of several subcortical centers, which, however, do not generate persistent fear memories. Here we show that the MRR also elicits fear, but this develops slowly over time, likely by plastic changes induced by the area and its connections. These findings assign a specific role to the MRR in fear learning. Particularly, we suggest that this area is responsible for the durable sensitization of fear circuits towards aversive contexts, and by this, it contributes to the persistence of fear memories. This suggests the existence a bottom-up control of fear circuits by the MRR, which complements the top-down control exerted by the medial prefrontal cortex.
Highlights
The optogenetic activation of the median raphe region (MRR) did not trigger freezing acutely, demonstrating that this brain region detaches from fear-effector systems, which elicit freezing when stimulated [1, 2]
MRR stimulation induced agitation that likely reflected its unpleasantness as shown by reduced exploration and shock-runs
MRR activation did not evoke conditioned fear responses the day, which indicates that MRR stimulation alone was not sufficient to form an associative memory that linked an adverse experience to a context
Summary
Due to its links to anxiety and post-traumatic stress disorder, the way in which adverse experience is transformed into persistent fear memories is a fundamental question in neuroscience. The premises of our hypothesis are as follows: (i) noxious stimuli–including those that are used as unconditioned stimuli in fear learning paradigms–strongly activate the MRR, (ii) the electrical stimulation of MRR induces either behavioral freezing or an unnatural forced movement, suggesting that the stimulation is aversive, and (iii) MRR hosts mechanisms that contribute significantly to fear-induced neural plasticity [3, 4, 6,7,8,9, 16] Based on these we hypothesized that MRR may per se elicit recent and/or remote fear responses. Halorhodopsin (NpHR)-mediated silencing of the MRR during electric shock-conditioning was used to test whether the effects of MRR stimulation are congruent with the role of this structure in classical fear conditioning
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