Though much attention has been given to the neural structures that underlie the long-term consolidation of contextual memories, little is known about the mechanisms responsible for the maintenance of memory precision. Here, we demonstrate a rapid time-dependent decline in memory precision in GABA B(1a) receptor knockout mice. First, we show that GABA B(1a) receptors are required for the maintenance, but not encoding, of a precise fear memory. We then demonstrate that GABA B(1a) receptors are required for the maintenance, but not encoding, of spatial memories. Our findings suggest that GABA-mediated presynaptic inhibition regulates the maintenance of memory precision as a function of memory age.Individuals suffering from post-traumatic stress disorder (PTSD) often come to re-experience the traumatic event in the presence of stimuli that were not present at the time of the trauma but bear some similarity to that event. Furthermore, this generalization of fear to neutral cues increases over time, so that a multiplicity of stimuli serves as a reminder for the original trauma (Riccio et al. 1984;Zhou and Riccio 1996;Wiltgen and Silva 2007;Lissek et al. 2008;Jasnow et al. 2012). In short, the fear memory becomes imprecise and is reactivated by cues not present at the time of learning. Using contextual fear conditioning and novel object training in rodents, the current study directly investigated the precision of both a fear and a nonfear memory in order to gain an understanding of how memory precision develops and is maintained over time.Contextual fear conditioning involves pairing a novel context (conditioned stimulus) with footshock (unconditioned stimulus) that serves to condition fear (assessed as freezing behavior) to that context. Many studies have demonstrated that shifting contextual cues shortly after contextual fear conditioning results in reduced freezing (i.e., the context shift effect). At early time points, rodents exhibit a contextually precise memory and can discriminate between the training and a neutral context. However, as the retention interval between training and testing increases, fear memories become less precise with animals exhibiting fear responses to neutral contexts (context specificity is lost 14-to 36-d post-training) (Zhou and Riccio 1996;Wiltgen and Silva 2007;Lissek et al. 2008;Jasnow et al. 2012). Though a significant amount of neurobehavioral research has investigated the mechanisms underlying the long-term consolidation of a contextual fear memory, very little is known about what underlies this loss in memory precision, or how memory precision is maintained over time.Recent evidence suggests that GABA B receptor-mediated presynaptic inhibition may play a role in stimulus discrimination. GABA B receptors are G protein-coupled receptors that exist as heterodimers containing two subunits, GABA B1 and GABA B2 (Gassmann and Bettler 2012). The GABA B1 receptor exists in two isoforms, GABA B(1a) and GABA B(1b) , with the isoforms being localized to presynaptic and postsynaptic termi...

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Acute social defeat represents a naturalistic form of conditioned fear and is an excellent model in which to investigate the biological basis of stress resilience. While there is growing interest in identifying biomarkers of stress resilience, until recently, it has not been feasible to associate levels of large numbers of neurochemicals and metabolites to stress-related phenotypes. The objective of the present study was to use an untargeted metabolomics approach to identify known and unknown neurochemicals in select brain regions that distinguish susceptible and resistant individuals in two rodent models of acute social defeat. In the first experiment, male mice were first phenotyped as resistant or susceptible. Then, mice were subjected to acute social defeat, and tissues were immediately collected from the ventromedial prefrontal cortex (vmPFC), basolateral/central amygdala (BLA/CeA), nucleus accumbens (NAc), and dorsal hippocampus (dHPC). Ultra-high performance liquid chromatography coupled with high resolution mass spectrometry (UPLC-HRMS) was used for the detection of water-soluble neurochemicals. In the second experiment, male Syrian hamsters were paired in daily agonistic encounters for 2 weeks, during which they formed stable dominant-subordinate relationships. Then, 24 h after the last dominance encounter, animals were exposed to acute social defeat stress. Immediately after social defeat, tissue was collected from the vmPFC, BLA/CeA, NAc, and dHPC for analysis using UPLC-HRMS. Although no single biomarker characterized stress-related phenotypes in both species, commonalities were found. For instance, in both model systems, animals resistant to social defeat stress also show increased concentration of molecules to protect against oxidative stress in the NAc and vmPFC. Additionally, in both mice and hamsters, unidentified spectral features were preliminarily annotated as potential targets for future experiments. Overall, these findings suggest that a metabolomics approach can identify functional groups of neurochemicals that may serve as novel targets for the diagnosis, treatment, or prevention of stress-related mental illness.

Aging is marked by an accumulation of damaged and modified brain proteins, and the ubiquitin-proteasome system (UPS) is important for cellular protein degradation. Recent work has established a critical role for the UPS in memory and synaptic plasticity, but the role of the UPS in age-related cognitive decline remains poorly understood. We trained young, middle-aged, and aged male and female rats using trace fear conditioning (TFC) to investigate the effects of age and sex on memory. We then measured markers of UPS-related protein degradation (phosphorylation of the Rpt6 proteasome regulatory subunit and K48-linked polyubiquitination) using western blots. We found that aged males, but not aged females, showed behavioral deficits at memory retrieval. Aged males also displayed reduced phosphorylation of the Rpt6 proteasome subunit and accumulation of K48 in the basolateral amygdala, while aged females displayed a similar pattern in the medial prefrontal cortex. These findings suggest that markers of UPS function are differentially affected by age and sex in a brain region-dependent manner. Together these results provide an important step toward understanding the UPS and circuit-level differences in aging males and females.

Brain derived neurotrophic factor (BDNF) plays a pivotal role in structural plasticity, learning, and memory. Electroencephalogram (EEG) spectral power in the cortex and hippocampus has also been correlated with learning and memory. In this study, we investigated the effect of globally reduced BDNF levels on learning behavior and EEG power via BDNF heterozygous (KO) rats. We employed several behavioral tests that are thought to depend on cortical and hippocampal plasticity to varying degrees: novel object recognition, a test that is reliant on a variety of cognitive systems; contextual fear, which is highly hippocampal-dependent; and cued fear, which has been shown to be amygdala-dependent. We also examined the effects of BDNF reduction on cortical and hippocampal EEG spectral power via chronically implanted electrodes in the motor cortex and dorsal hippocampus. We found that BDNF KO rats were impaired in novelty recognition and fear memory retention, while hippocampal EEG power was decreased in slow waves and increased in fast waves. Interestingly, our results, for the first time, show sexual dimorphism in each of our tests. These results support the hypothesis that BDNF drives both cognitive plasticity and coordinates EEG activity patterns, potentially serving as a link between the two.