Neurobiological correlates of state-dependent context fear

Abstract

Retrieval of fear memories can be state-dependent, meaning that they are best retrieved if the brain states at encoding and retrieval are similar. Such states can be induced by activating extrasynaptic γ-aminobutyric acid type A receptors (GABAR) with the broad α-subunit activator gaboxadol. However, the circuit mechanisms and specific subunits underlying gaboxadol's effects are not well understood. Here we show that gaboxadol induces profound changes of local and network oscillatory activity, indicative of discoordinated hippocampal-cortical activity, that were accompanied by robust and long-lasting state-dependent conditioned fear. Episodic memories typically are hippocampus-dependent for a limited period after learning, but become cortex-dependent with the passage of time. In contrast, state-dependent memories continued to rely on hippocampal GABAergic mechanisms for memory retrieval. Pharmacological approaches with α-subunit-specific agonists targeting the hippocampus implicated the prototypic extrasynaptic subunits (α) as the mediator of state-dependent conditioned fear. Together, our findings suggest that continued dependence on hippocampal rather than cortical mechanisms could be an important feature of state-dependent memories that contributes to their conditional retrieval.

Mammillary body regulates state-dependent fear by alternating cortical oscillations

“…For example, while theta rhythm is a dominant pattern of local field potential (LFP) during voluntary behavior as well as rapid-eye-movement (REM) sleep 12 , 13 , delta oscillations are the hallmark of deep sleep, contributing to memory consolidation 14 , 15 . Moreover, recent study has also shown that GABA A receptor agonist gaboxadol, a previously proved state-dependent learning inducing drug, significantly enhances hippocampal delta power 5 , 16 , suggesting brain oscillations may be associated with the phenomenon of state-dependent memory.…”

State-Dependent Memory: Neurobiological Advances and Prospects for Translation to Dissociative Amnesia

“…Changes in the hippocampus, which is known to play important roles in processing both conscious and unconscious memories (Henke, 2010 ; Hannula and Greene, 2012 ; Shohamy and Turk-Browne, 2013 ), may be particularly relevant. A notable change within the hippocampus and cortex during SDM encoding under heightened tonic inhibition (using systemic infusion of the drug gaboxadol) is the increase in power of slow, delta oscillations, along with a decrease of theta and gamma oscillations (Meyer et al, 2017 ). At the same time, at the circuit level, the connectivity between the hippocampus and neocortical areas (retrosplenial, entorhinal and anterior cingulate cortex) is significantly reduced (Jovasevic et al, 2015 ; Meyer et al, 2017 ).…”

“…A notable change within the hippocampus and cortex during SDM encoding under heightened tonic inhibition (using systemic infusion of the drug gaboxadol) is the increase in power of slow, delta oscillations, along with a decrease of theta and gamma oscillations (Meyer et al, 2017 ). At the same time, at the circuit level, the connectivity between the hippocampus and neocortical areas (retrosplenial, entorhinal and anterior cingulate cortex) is significantly reduced (Jovasevic et al, 2015 ; Meyer et al, 2017 ). Consistent with these observations, it was recently found that enhanced cortical delta oscillations causally contribute to the formation of state-dependent fear-inducing context memories during states of reduced excitation (using systemic administration of the NMDA receptor antagonist MK-801; Jiang et al, 2018 ).…”

Stress-related memories disrupt sociability and associated patterning of hippocampal activity: a role of hilar oxytocin receptor-positive interneurons

“…Rodent models of stress-enhanced state-dependent fear conditioning (S-SDFC) and state-dependent fear conditioning (SDFC) allow studying the impact of stressrelated memories on social behavior. Whereas increasing stress exposure strengthens the encoding of fear-inducing memory [9][10][11][12][13] , state-dependent encoding restricts memory access to specific brain states 14,15 . State-dependent memory is readily induced in mice trained on gaboxadol (GBX), an agonist of extrasynaptic GABA A R 16 that enhances tonic inhibition in the DG 17 .…”

“…State-dependent memory is readily induced in mice trained on gaboxadol (GBX), an agonist of extrasynaptic GABA A R 16 that enhances tonic inhibition in the DG 17 . Although such memories are normally not accessible to retrieval, their presence can be demonstrated when mice are tested in the presence of the drug 14 , 15 . Furthermore, in this model, stress-related fear memories seem to be inhibited by cortical mechanisms and preferentially processed by hippocampal–lateral septal (LS) circuits 14 .…”