Extinction reverses olfactory fear-conditioned increases in neuron number and glomerular size

Abstract

Although much work has investigated the contribution of brain regions such as the amygdala, hippocampus, and prefrontal cortex to the processing of fear learning and memory, fewer studies have examined the role of sensory systems, in particular the olfactory system, in the detection and perception of cues involved in learning and memory. The primary sensory receptive field maps of the olfactory system are exquisitely organized and respond dynamically to cues in the environment, remaining plastic from development through adulthood. We have previously demonstrated that olfactory fear conditioning leads to increased odorant-specific receptor representation in the main olfactory epithelium and in glomeruli within the olfactory bulb. We now demonstrate that olfactory extinction training specific to the conditioned odor stimulus reverses the conditioning-associated freezing behavior and odor learning-induced structural changes in the olfactory epithelium and olfactory bulb in an odorant ligand-specific manner. These data suggest that learninginduced freezing behavior, structural alterations, and enhanced neural sensory representation can be reversed in adult mice following extinction training.fear extinction | olfaction | neural plasticity I ncreasing evidence suggests that the cellular, neuroanatomical, and receptive field organizations of vertebrate sensory systems are continually reshaped throughout adulthood by cues from the external environment. Activity-dependent changes are known to occur both during critical periods of development and also in the adult brain, allowing the animal to optimally perform behaviors based on the demands of the surrounding environment. Postmitotic organizational changes, along with activity-dependent plasticity, have been largely implicated in shaping sensory circuits from development through adulthood (1-4). In particular, the olfactory sensory system of adult mice exhibits functional and neuroanatomical learning-dependent changes following olfactory fear conditioning in adulthood (5-7). The M71-LacZ transgenic mouse line expresses LacZ under the M71 odorant receptor (OR) promoter (encoded by the olfactory receptor 151 gene, Olfr151) (8) in the M71 OR-expressing, acetophenone-responsive population of olfactory sensory neurons (OSNs). Using this line, we previously demonstrated an increased number of M71-expressing OSNs in the main olfactory epithelium (MOE) of adult mice following olfactory fear conditioning to acetophenone (5, 7), an odorant that activates the M71/M72 ORs (9, 10). This increase in receptor-specific OSNs within the MOE was directly correlated with an increase in the area of M71+ axons innervating the M71 glomeruli within the olfactory bulbs (OBs). Behaviorally, these olfactory fear-conditioned mice also exhibited enhanced fear-potentiated startle (FPS) and freezing specific to the conditioned odor stimulus. Notably such changes were never seen with equivalent odorant exposure alone but only when the odorant was paired with an aversive or appetitive cue (5, 7), sugges...

Analysis of Genetically Regulated Gene Expression identifies a trauma type specific PTSD gene, SNRNP35

“…A number of the M-PTSD specific functional enrichments are also highly plausible; for example, enrichment H3K27 acetylation peaks from a gene-set derived from DLPFC neurons (Girdhar et al, 2018), known to have a role in stress models and neuropsychiatric disorders (McEwen et al, 2015), including PTSD (Maddox et al, 2018). Our results highlight a potential shared genetic basis between olfaction and M-PTSD, in line with previous findings of differential olfactory 5 identification in individuals with combat-related M-PTSD compared to healthy controls (Vasterling et al, 2000); olfactory triggers for PTSD intrusion symptoms (Daniels and Vermetten, 2016); olfactory-based treatments for PTSD (Aiken and Berry, 2015); and the key role of olfaction in fear conditioning in animal models (Morrison et al, 2015). Given the significant genetic overlap between olfaction and PTSD, our results support the hypothesis that 10 differential sensitivity to odors may predispose to development of PTSD.…”

Proximate causes and consequences of intergenerational influences of salient sensory experience

“…The olfactory system is an ideal system to successfully address how experience with a salient environmental cue can exert influences across generations . Training mice to associate a specific odor (eg, Odor A) with a mild foot‐shock results in these mice developing fearful behavior toward Odor A and possessing increased neuroanatomical expression of odorant receptors that detect Odor A . From an intergenerational perspective, we have demonstrated that after mice have been exposed to Odor A + shock conditioning their naïve offspring possess a sensitivity to Odor A and increased neuroanatomical expression of odorant receptors that detect Odor A .…”

Semiochemical responsive olfactory sensory neurons are sexually dimorphic and plastic

“…Additionally, the form of plasticity we observe appears to employ a distinct mechanism from reports of fear conditioning influencing the proportional abundance of OSNs expressing ORs responsive to the fear-conditioned odor 29–31 . In the case of fear conditioning to acetophenone, the number of OSNs expressing M71 appears to profoundly upregulate within just 3 weeks.…”