Enhanced contextual fear memory in central serotonin-deficient mice

Abstract

Central serotonin (5-HT) dysregulation contributes to the susceptibility for mental disorders, including depression, anxiety, and posttraumatic stress disorder, and learning and memory deficits. We report that the formation of hippocampus-dependent spatial memory is compromised, but the acquisition and retrieval of contextual fear memory are enhanced, in central 5-HT-deficient mice. Genetic deletion of serotonin in the brain was achieved by inactivating Lmx1b selectively in the raphe nuclei of the brainstem, resulting in a near-complete loss of 5-HT throughout the brain. These 5-HT-deficient mice exhibited no gross abnormality in brain structures and had normal locomotor activity. Spatial learning in the Morris water maze was unaffected, but the retrieval of spatial memory was impaired. In contrast, contextual fear learning and memory induced by foot-shock conditioning was markedly enhanced, but this enhancement could be prevented by intracerebroventricular administration of 5-HT. Foot shock impaired longterm potentiation and facilitated long-term depression in hippocampal slices in WT mice but had no effect in 5-HT-deficient mice. Furthermore, bath application of 5-HT in 5-HT-deficient mice restored foot shock-induced alterations of hippocampal synaptic plasticity. Thus, central 5-HT regulates hippocampus-dependent contextual fear memory, and 5-HT modulation of hippocampal synaptic plasticity may be the underlying mechanism. The enhanced fear memory in 5-HT-deficient mice supports the notion that 5-HT deficiency confers susceptibility to posttraumatic stress disorder in humans.hippocampus ͉ long-term depression ͉ long-term potentiation ͉ anxiety T he neurotransmitter serotonin (5-HT) exerts a wide spectrum of actions in the nervous system by modulating neural development, synaptic plasticity, pain sensation, rhythm, food intake, and a variety of behaviors (1-4). It has been proposed that perturbation of the 5-HT level in the brain contributes to depression and anxiety, and posttraumatic stress disorder (PTSD) (5-8), which are often accompanied by learning and memory deficits (9-11). The hippocampus is known to be critical for the formation of spatial and contextual fear memories (12-15), and the retrieval of hippocampus-dependent memories was found to be impaired in patients with depression and PTSD (16)(17)(18). Recent studies have also implicated the hippocampus as one of the primary sites for antidepressants (6,(19)(20)(21)(22)(23). Aversive stimuli such as foot shock that led to anxiety, depression, and fear memory in rodents also altered activity-dependent hippocampal synaptic plasticity (24)(25)(26)(27)(28)(29). Because the modulation of 5-HT activity altered hippocampal long-term potentiation (LTP) and long-term depression (LTD) (30-32), it is possible that perturbation of 5-HT level in the brain may affect hippocampusdependent learning and memory, and changes in hippocampal synaptic plasticity may also contribute to mental disorders, including anxiety and fear memory.Inhibitors of 5-HT biosynthesis that...

Severe Serotonin Depletion after Conditional Deletion of the Vesicular Monoamine Transporter 2 Gene in Serotonin Neurons: Neural and Behavioral Consequences

“…This finding is in agreement with reports in several genetic models of 5-HT-deficient mice (Dai et al, 2008;Kiyasova et al, 2011) and with numerous studies using pharmacological approaches to decrease brain 5-HT in rats (Graeff, 2004;Griebel, 1995). Furthermore, decreased 5-HT input at several receptors (including the 5-HT 2A and 5-HT 2C subtypes) clearly reduces anxiety in mice (Heisler et al, 2007;Mongeau et al, 2010;Weisstaub et al, 2006).…”

“…In the NSF, which involves a conflict between the drive to feed and risk assessment behaviors triggered by the unfamiliar environment, VMAT2 sertÀcre mice showed an anxiolytic-like behavioral profile. This agrees with the anxiolytic-like effect of PCPA-induced 5-HT depletion and with observations in other 5-HT depleted mutant mice (Dai et al, 2008;Kiyasova et al, 2011).…”

“…All recent genetic hyposerotonergic models focused on reducing 5-HT production either by targeting the central 5-HT synthesis enzyme, TPH2 (Alenina et al, 2009;Beaulieu et al, 2008;Gutknecht et al, 2008;Savelieva et al, 2008) or by invalidating the transcription factors controlling differentiation of raphe neurons such as pet1 and lmx1B (Dai et al, 2008;Hendricks et al, 2003;Kiyasova et al, 2011;Zhao et al, 2006). The more severe 5-HT depletion observed here (À95%), compared with previous models (À70 to 90%), is likely due to the fact that increased 5-HT degradation, when VMAT2 is absent, affects all sources of 5-HT (eg, produced by TPH1/TPH2).…”

Genetic Models of Serotonin (5‐HT) Depletion: What do They Tell Us About the Developmental Role of 5‐HT?

“…The conditional Lmx1b À/À mice also exhibit some behavioral abnormalities as adults (Dai et al, 2008). They have impaired retrieval of spatial memory, as tested in the Morris water maze.…”

Differentiation of Primary Emotions through Neuromodulators: Review of Literature

“…It has been found that l-tryptophan depresses while levodopa intensifies emotional reactivity, the former lowering the level of endogenous 5-HT. And it was also found that lack of 5-HT enhances the emotional reactivity to learned fear memories [34] . So the major benefit of the 5-HT drug is alleviated anxiety and improved sleep.…”