The anterior cingulate cortex and its role in controlling contextual fear memory to predatory threats

Predator exposure is a life-threatening experience and elicits learned fear responses to the context in which the predator was encountered. The anterior cingulate area (ACA) occupies a pivotal position in a cortical network responsive to predatory threats, and it exerts a critical role in processing fear memory. The experiments were made in mice and revealed that the ACA is involved in both the acquisition and expression of contextual fear to predatory threat. Overall, the ACA can provide predictive relationships between the context and the predator threat and influences fear memory acquisition through projections to the basolateral amygdala and perirhinal region and the expression of contextual fear through projections to the dorsolateral periaqueductal gray. Our results expand previous studies based on classical fear conditioning and open interesting perspectives for understanding how the ACA is involved in processing contextual fear memory to ethologic threatening conditions that entrain specific medial hypothalamic fear circuits.

Morris Water Maze and Contextual Fear Conditioning Tasks to Evaluate Cognitive Functions Associated With Adult Hippocampal Neurogenesis

New neurons are continuously generated and functionally integrated into the dentate gyrus (DG) network during the adult lifespan of most mammals. The hippocampus is a crucial structure for spatial learning and memory, and the addition of new neurons into the DG circuitry of rodents seems to be a key element for these processes to occur. The Morris water maze (MWM) and contextual fear conditioning (CFC) are among the most commonly used hippocampus-dependent behavioral tasks to study episodic-like learning and memory in rodents. While the functional contribution of adult hippocampal neurogenesis (AHN) through these paradigms has been widely addressed, results have generated controversial findings. In this review, we analyze and discuss possible factors in the experimental methods that could explain the inconsistent results among AHN studies; moreover, we provide specific suggestions for the design of more sensitive protocols to assess AHN-mediated learning and memory functions.

Differential Effects of Lateral and Medial Entorhinal Cortex Lesions on Trace, Delay and Contextual Fear Memories

The entorhinal cortex (EC), with connections to the hippocampus, amygdala, and neocortex, is a critical, yet still underexplored, contributor to fear memory. Previous research suggests possible heterogeneity of function among its lateral (LEC) and medial (MEC) subregions. However, it is not well established what unique roles these subregions serve as the literature has shown mixed results depending on target of manipulation and type of conditioning used. Few studies have manipulated both the LEC and MEC within the same experiment. The present experiment systematically manipulated LEC and MEC function to examine their potential roles in fear memory expression. Long-Evans rats were trained using either trace or delay fear conditioning. The following day, rats received an N-methyl-D-aspartate (NMDA)-induced lesion to the LEC or MEC or received a sham surgery. Following recovery, rats were given an 8-min context test in the original context. The next day, rats were tested for tone freezing in a novel context with three discrete tone presentations. Further, rats were tested for hyperactivity in an open field under both dark and bright light gradient conditions. Results: Following either LEC or MEC lesion, freezing to context was significantly reduced in both trace and delay conditioned rats. LEC-lesioned rats consistently showed significantly less freezing following tone-offset (trace interval, or equivalent, and intertrial interval) in both trace and delay fear conditioned rats. Conclusions: These data suggest that the LEC may play a role in the expression of a conjunctive representation between the tone and context that mediates the maintenance of post-tone freezing.

Remote contextual fear retrieval engages activity from salience network regions in rats

The ability to retrieve contextual fear memories depends on the coordinated activation of a brain-wide circuitry. Transition from recent to remote memories seems to involve the reorganization of this circuitry, a process called systems consolidation that has been associated with time-dependent fear generalization. However, it is not known whether emotional memories acquired under different levels of stress can undergo different systems consolidation processes. Here, we explored the activation pattern and functional connectivity of key brain regions associated with contextual fear conditioning (CFC) retrieval after recent (2 days) or remote (28 days) memory tests performed in rats submitted to strong (1.0mA footshock) or mild (0.3mA footshock) training. We used brain tissue from Wistar rats from a previous study, where we observed that increasing training intensity promotes fear memory generalization over time, possibly due to an increase in corticosterone levels during memory consolidation. Analysis of Fos expression across 8 regions of interest (ROIs) allowed us to identify coactivation between them at both timepoints following memory recall. Our results showed that strong CFC elicits higher Fos activation in the anterior insular and prelimbic cortices during remote retrieval, which was - along with the basolateral amygdala - positively correlated with freezing. Rats trained either with mild or strong CFC showed a broad functional connectivity at the recent timepoint whereas only animals submitted to the strong CFC showed a widespread loss of coactivation during remote retrieval. Our findings suggest that increasing training intensity results in differential processes of systems consolidation, possibly associated with increased post-training corticosterone release, and that strong CFC engages activity from areas associated with the salience network during remote retrieval.

Hippocampal neurons’ cytosolic and membrane-bound ribosomal transcript profiles are differentially regulated by learning and subsequent sleep

The hippocampus is essential for consolidating transient experiences into long-lasting memories. Memory consolidation is facilitated by postlearning sleep, although the underlying cellular mechanisms are largely unknown. We took an unbiased approach to this question by using a mouse model of hippocampally mediated, sleep-dependent memory consolidation (contextual fear memory). Because synaptic plasticity is associated with changes to both neuronal cell membranes (e.g., receptors) and cytosol (e.g., cytoskeletal elements), we characterized how these cell compartments are affected by learning and subsequent sleep or sleep deprivation (SD). Translating ribosome affinity purification was used to profile ribosome-associated RNAs in different subcellular compartments (cytosol and membrane) and in different cell populations (whole hippocampus, Camk2a+ neurons, or highly active neurons with phosphorylated ribosomal subunit S6 [pS6+]). We examined how transcript profiles change as a function of sleep versus SD and prior learning (contextual fear conditioning; CFC). While sleep loss altered many cytosolic ribosomal transcripts, CFC altered almost none, and CFC-driven changes were occluded by subsequent SD. In striking contrast, SD altered few transcripts on membrane-bound (MB) ribosomes, while learning altered many more (including long non-coding RNAs [lncRNAs]). The cellular pathways most affected by CFC were involved in structural remodeling. Comparisons of post-CFC MB transcript profiles between sleeping and SD mice implicated changes in cellular metabolism in Camk2a+ neurons and protein synthesis in highly active pS6+ (putative “engram”) neurons as biological processes disrupted by SD. These findings provide insights into how learning affects hippocampal neurons and suggest that the effects of SD on memory consolidation are cell type and subcellular compartment specific.