GABAergic mechanisms regulated by miR-33 encode state-dependent fear

Abstract

Fear-inducing memories can be state dependent, meaning that they can best be retrieved if the brain states at encoding and retrieval are similar. Restricted access to such memories can present a risk for psychiatric disorders and hamper their treatment. To better understand the mechanisms underlying state-dependent fear, we used a mouse model of contextual fear conditioning. We found that heightened activity of hippocampal extrasynaptic GABAA receptors, believed to impair fear and memory, actually enabled their state-dependent encoding and retrieval. This effect required protein kinase C-βII and was influenced by miR-33, a microRNA that regulates several GABA-related proteins. In the extended hippocampal circuit, extrasynaptic GABAA receptors promoted subcortical, but impaired cortical, activation during memory encoding of context fear. Moreover, suppression of retrosplenial cortical activity, which normally impairs retrieval, had an enhancing effect on the retrieval of state-dependent fear. These mechanisms can serve as treatment targets for managing access to state-dependent memories of stressful experiences.

Acute Sleep Deprivation Blocks Short- and Long-Term Operant Memory inAplysia

“…State dependence of memory has been demonstrated for aversive fear memory, emotional memory, and drug-related behaviors. 96,97 In the desert locust, decision making in an odor-associated food choice test occurs based on a state-dependent valuation of the choices 98 It is possible that the effects of sleep deprivation that we observed on long-term memory in Aplysia were state dependent, with the neuronal effects of sleep deprivation incorporated as part of the learning context. In mice, memory impairments due to sleep deprivation of REM sleep can be state dependent.…”

Polymorphisms that affect GABA neurotransmission predict processing of aversive prediction errors in humans

“…One possible candidate is GABA, the most common inhibitory neurotransmitter in our nervous system (Steighart, 1995). Animal studies suggest that GABA plays an important role in learning (Botta et al, 2015;Jovasevic et al, 2015). Importantly, there is evidence that prediction error signalling during learning seems to involve GABA (Kim et al, 1998).…”

“…The A allele has been shown to be associated with increased mRNA expression (Zhao et al, 2006), and is in strong linkage disequilibrium with rs1816071 (D' = .93; r 2 = .87), which has also been shown to be associated with gene expression (Zhao et al, 2006(Zhao et al, , 2009. The GABRB2 gene is also a promising candidate, as GABAA receptors are involved in fear learning (Brown et al, 2012), and mRNA expression of the GABRB2 gene changes following fear conditioning in mice (Jovasevic et al, 2015).…”

Muscarinic acetylcholine receptors act in synergy to facilitate learning and memory

“…We also believe it to be unlikely that general effects would have resulted in region-and memory phase-specific reductions of freezing. Finally, some of the freezing impairments might have been due to state-dependent effects, but that can be ruled out, because the dose of scopolamine used in this study does not produce such effects in the contextual fear conditioning paradigm (Jovasevic et al 2015). Notably, cholinergic drugs can also interfere with behavior by increasing anxiety (Smythe et al 1998).…”

“…In previous studies, we have shown that single infusions of pharmacological agents at these coordinates can have profound effects on memory processes (Corcoran et al 2011(Corcoran et al , 2013Leaderbrand et al 2014;Jovasevic et al 2015). Cannulas were fixed in place with dental cement, and mice were allowed to recover for at least 72 h prior to behavior experiments or viral infusions.…”