Suppression of conditioning to ambiguous cues by pharmacogenetic inhibition of the dentate gyrus

Abstract

Serotonin receptor 1A knockout (Htr1a(KO)) mice show increased anxiety-related behavior in tests measuring innate avoidance. Here we demonstrate that Htr1a(KO) mice show enhanced fear conditioning to ambiguous conditioned stimuli, a hallmark of human anxiety. To examine the involvement of specific forebrain circuits in this phenotype, we developed a pharmacogenetic technique for the rapid tissue- and cell type-specific silencing of neural activity in vivo. Inhibition of neurons in the central nucleus of the amygdala suppressed conditioned responses to both ambiguous and nonambiguous cues. In contrast, inhibition of hippocampal dentate gyrus granule cells selectively suppressed conditioned responses to ambiguous cues and reversed the knockout phenotype. These data demonstrate that Htr1a(KO) mice have a bias in the processing of threatening cues that is moderated by hippocampal mossy-fiber circuits, and suggest that the hippocampus is important in the response to ambiguous aversive stimuli.

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

“…Contrariwise, deleting the 5-HT1A-R only in adulthood had no effect on anxiety-like behavior. Using a simple pharmacological approach, the fear-bias to ambiguity was mimicked in nonmutant mice by treatment with a 5-HT1A-R antagonist (WAY 100635) during the third and fourth postnatal weeks (Tsetsenis et al, 2007). These data again speak to the importance of serotonin as a factor driving the development of the corticolimbic systems subserving the stress response later in life (for further discussion, see Ansorge et al, 2007;Gross and Hen, 2004;Hariri and Holmes, 2006).…”

“…Further extending the phenotypic profile of the 5-HT1A-R knockout mouse, Gross and colleagues have recently demonstrated that these mice have a fear bias towards environmental cues that are ambiguous predictors of trauma and which produce little fear in non-mutant mice (Klemenhagen et al, 2006;Tsetsenis et al, 2007). 5-HT1A-Rs are expressed on pyramidal neurons in the hippocampus (Chalmers and Watson, 1991;Clement et al, 1996;Khawaja, 1995;Kia et al, 1996aKia et al, , 1996bRaurich et al, 1999;Wright et al, 1995) where they exert an inhibitory action (Corradetti et al, 1998).…”

“…5-HT1A-Rs are expressed on pyramidal neurons in the hippocampus (Chalmers and Watson, 1991;Clement et al, 1996;Khawaja, 1995;Kia et al, 1996aKia et al, , 1996bRaurich et al, 1999;Wright et al, 1995) where they exert an inhibitory action (Corradetti et al, 1998). 5-HT1A-R knockout mice display signs of hippocampal hyperexcitability (Sibille et al, 2000) and Tsetsenis et al found that inhibition of cells within the dentate gyrus subregion of the hippocampus was sufficient to normalize the abnormal fear bias in the knockouts (Tsetsenis et al, 2007). While the hippocampus is not a focus of the current review, these findings are consonant with the idea that the hippocampus works in concert with the PFC and amygdala to gate environmental information regarding the precise stimulus features of threatening stimuli (Maren and Quirk, 2004;McHugh et al, 2007) (see also Gray and McNaughton, 1996).…”

Genetic Strain Differences in Learned Fear Inhibition Associated with Variation in Neuroendocrine, Autonomic, and Amygdala Dendritic Phenotypes

“…Partially reinforced cued fear discrimination was tested as previously described (Tsetsenis et al, 2007). Mice received a single training session in Cxt A (as above).…”

A test to identify judgement bias in mice

“…Recently, the phenomenon of judgement bias has been investigated in several animal species, some being aimed at welfare assessment while others are more interested in judgement bias in animal models of human affective disorders [12][13][14][15][16][17][18][19][20][21][22][23].…”