Patterns of Coupled Theta Activity in Amygdala-Hippocampal-Prefrontal Cortical Circuits during Fear Extinction

Abstract

Signals related to fear memory and extinction are processed within brain pathways involving the lateral amygdala (LA) for formation of aversive stimulus associations, the CA1 area of the hippocampus for context-dependent modulation of these associations, and the infralimbic region of the medial prefrontal cortex (mPFC) for extinction processes. While many studies have addressed the contribution of each of these modules individually, little is known about their interactions and how they function as an integrated system. Here we show, by combining multiple site local field potential (LFP) and unit recordings in freely behaving mice in a fear conditioning paradigm, that theta oscillations may provide a means for temporally and functionally connecting these modules. Theta oscillations occurred with high specificity in the CA1-LA-mPFC network. Theta coupling increased between all areas during retrieval of conditioned fear, and declined during extinction learning. During extinction recall, theta coupling partly rebounded in LA-mPFC and CA1-mPFC, and remained at a low level in CA1-LA. Interfering with theta coupling through local electrical microstimulation in CA1-LA affected conditioned fear and extinction recall depending on theta phase. These results support the hypothesis that theta coupling provides a means for inter-areal coordination in conditioned behavioral responsiveness. More specifically, theta oscillations seem to contribute to a population code indicating conditioned stimuli during recall of fear memory before and after extinction.

Stress during puberty boosts metabolic activation associated with fear-extinction learning in hippocampus, basal amygdala and cingulate cortex

“…Additionally, correlational analysis of our data revealed that only stressed males showed a significant association between freezing during tone and the metabolic activation of hippocampus, basolateral amygdala and PVN. These results are consistent with previous studies showing a synchronization of the theta frequency range between basolateral amygdala and hippocampus during fear memory retrieval (Seidenbecher, Laxmi, Stork, & Pape, 2003) that declines during extinction learning (Lesting et al, 2011). Indeed, in our case we found a highly significant correlation between the metabolic activation of the hippocampus and the basolateral amygdala during extinction in stressed males and females, but not in the non-stressed groups.…”

Resolving the neural circuits of anxiety

“…Conversely, artificial theta synchronization of LA and HPC during extinction recall (such that PFC firing no longer leads these rhythms) increases freezing to the CS 137 . BLA field potentials and spike activity are entrained to the mPFC theta rhythm during periods of perceived safety (e.g., when mice enter the relative safety of the periphery of the open field 32 ).…”

Observation of Distressed Conspecific as a Model of Emotional Trauma Generates Silent Synapses in the Prefrontal-Amygdala Pathway and Enhances Fear Learning, but Ketamine Abolishes those Effects

“…Elevated c-Fos expression in dmPFC and BLA after OF indicated that modifications may involve the dmPFC-BLA Emotional trauma generates silent synapses W Ito et al pathway. Given the dmPFC-BLA interactions are required for PA learning (Malin et al, 2007;Malin and McGaugh, 2006) and correlate with fear memory (Lesting et al, 2011;Popa et al, 2010), the formation of new silent synapses is a potential mechanism to enhance PA learning via strengthening dmPFC-BLA connectivity.…”

“…Emotionally salient stimuli generally recruit the dorsomedial prefrontal cortex (dmPFC) and the basolateral amygdala (BLA), which have strong reciprocal projections (Hubner et al, 2014;McDonald, 1998) and are involved in fear learning (Gilmartin et al, 2014;Marek et al, 2013;Senn et al, 2014), including contextual learning during observational fear (Amano et al, 2010;Jeon et al, 2010). Fear learning increases oscillatory synchronization between the two structures (Lesting et al, 2011;Likhtik et al, 2014;Stujenske et al, 2014), the amplitude of which correlates with the strength of fear memory (Popa et al, 2010). On the other hand, synaptic inputs from the medial prefrontal cortex to BLA excitatory neurons become attenuated after fear extinction (Cho et al, 2013).…”