Theta-frequency (4–12 Hz) oscillations were first isolated and came of age as an important concept in neurophysiology in the dorsal hippocampus (dHPC). Extensive work on hippocampal theta oscillations has demonstrated how theta is generated via the interplay of precisely timed inputs. It has led to the notion of inhibition as a theta pacemaker, and clarified the role theta has in organizing cell activity and other oscillations. During behavior, hippocampal theta has been implicated in creating windows for Hebbian plasticity, as well as organizing neural coding for memory formation and spatial navigation. This review focuses on theta oscillations in fear and anxiety, a topic of recently increased interest.
Initial efforts at characterizing the role of theta in fear began with an examination of theta oscillations in the amygdala and related structures. For example, pyramidal cells of the basolateral amygdala (BLA) show a prominent theta oscillation and have a combination of ionic conductances that allow cells to intrinsically resonate at the theta frequency (Pape and Driesang, 1998). Furthermore, the amygdala shows increased theta activity and synchrony with the hippocampus during presentation of fear-conditioned stimuli (Seidenbecher et al, 2003). Similarly, hippocampal recordings have shown that in the ventral (vHPC) but not dorsal hippocampus, theta increases with innate anxiety (Adhikari et al, 2011), indicating that theta modulates anxiety in the vHPC separately from spatial navigation in the dHPC.
Recent studies focusing on theta in circuit-level communication during fear and safety suggest that it may open temporary windows of communication between areas. Simultaneous recordings show increased theta-range synchrony between the BLA and hippocampus during presentations of fear-conditioned stimuli and in sleep after fear conditioning, possibly aiding memory consolidation (Seidenbecher et al, 2003; Popa et al, 2010). Similarly, recordings in the vHPC and prefrontal cortex (mPFC) demonstrate increased theta-frequency synchrony between the two regions during anxiety. Moreover, mPFC neurons become more phase-locked to vHPC theta input with elevated anxiety (Adhikari et al, 2011), indicating that vHPC sends information about anxiety to the mPFC.
Interestingly, as fear subsides during extinction of conditioned fear, BLA–mPFC theta synchrony increases (Lesting et al, 2011), indicating that prefrontal inputs to the amygdala use theta as a mechanism for communicating safety. Indeed, neural firing in the BLA becomes entrained to incoming mPFC theta only when animals are presented with conditioned stimuli that are recognized as safe or when animals are in the relative safety of the periphery in the otherwise aversive open field (EL and JAG, unpublished observations). Thus, mPFC–BLA synchrony increases and cellular networks in the BLA are entrained to theta input from the mPFC when animals actively recognize safety, likely driving local inhibitory networks that decrease fear.
Recent evidence shows that interneurons in the BLA can be organized by hippocampal theta (Bienvenu et al, 2012), opening the possibility that the same could be true for prefrontal inputs. Therefore, entrainment of BLA cell assemblies by mPFC theta input could organize local inhibitory circuits of the BLA to provide an effective mechanism for the mPFC to signal safety.
FUNDING AND DISCLOSURE
The authors declare no conflict of interest.
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Dr Likhtik’s research was supported by F32 MH088103 from the NIH, and Charles H Revson Foundation. Dr Gordon’s research has been funded by the NIH (R01 MH081968 and P50 MH096891), the Hope for Depression Research Foundation and the International Mental Health Research Organization.
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Likhtik, E., Gordon, J. Circuits in Sync: Decoding Theta Communication in Fear and Safety. Neuropsychopharmacol 39, 235–236 (2014). https://doi.org/10.1038/npp.2013.228
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