Differential impacts of advanced age and sex in age-related trace fear memory impairment in rats.

While cognitive function remains stable for majority of the lifespan, many functions sharply decline in later life. Women have higher rates of neurodegenerative diseases that involve memory loss, including Alzheimer's disease. This sex disparity may be due to longer life expectancies when compared to men; women outlive men by roughly 5 years globally.

Context controls the ability of unconditional stimulus deflation to mitigate fear relapse.

Our lab, and others, have recently demonstrated that fear behavior can be weakened following fear acquisition with a footshock unconditional stimulus by presenting a weaker version of that footshock, a phenomenon termed 'unconditional stimulus deflation' or US deflation. Unlike extinction, US deflation putatively functions by modifying the original fear memory, potentially making it a more effective candidate for reducing fear and preventing relapse effects often observed following extinction. Here, we adapted our contextual fear US deflation procedure to a delay conditioning paradigm in order to examine common relapse phenomena: renewal and reinstatement.

The consequences of stress on the brain and fear.

A region of the brain called the paraventricular thalamus mediates the impact of stress on unlearned fear responses, but is not involved in learned fear behavior.

The interval between conditional stimulus onset and unconditional stimulus onset, not training-to-test interval, determines patterns of immediate early gene expression in the anterior retrosplenial cortex.

Prior work has found that the retrosplenial cortex (RSC) is necessary for formation and retrieval of trace, but not delay, fear conditioning. However, more recently, others have demonstrated that activity in the retrosplenial cortex is necessary for retrieval of a remotely-acquired delay fear memory, suggesting that as memory undergoes systems consolidation it becomes more dependent on neural activity in the RSC. Here, we aimed to examine expression of the immediate early gene zif268 in two distinct subregions of the retrosplenial cortex (anterior and posterior) following retrieval of either a recently-acquired or remotely-acquired delay fear memory.

Stress-enhanced fear learning can be reduced with unconditional stimulus deflation with constraints.

Exposure to extreme stress can negatively impact behavior and lead to prolonged fear sensitization. These processes can be studied in the lab using stress-enhanced fear learning (SEFL), where prior exposure to inescapable stress exacerbates later contextual fear conditioning. A common method to reduce conditional fear is through extinction, where a conditional stimulus once paired with an unconditional (US; e.

Corrigendum: Generalization and discrimination of inhibitory avoidance differentially engage anterior and posterior retrosplenial subregions.

[This corrects the article DOI: 10.3389/fnbeh.2024.

Dysregulation of baseline and learning-dependent protein degradation in the aged hippocampus.

The ubiquitin-proteasome system (UPS) controls the majority of protein degradation in cells and dysregulation of the UPS has been implicated in the pathophysiology of numerous neurodegenerative disorders, including Alzheimer's disease. Further, strong evidence supports a critical role for the UPS in synaptic plasticity and memory formation. However, while proteasome function is known to decrease broadly in the brain across the lifespan, whether it changes in the hippocampus, a region critical for memory storage and among the first impacted in Alzheimer's disease, at rest and following learning in the aged brain remains unknown.

Behavioral outputs and overlapping circuits between conditional fear and active avoidance.

Aversive learning can produce a wide variety of defensive behavioral responses depending on the circumstances, ranging from reactive responses like freezing to proactive avoidance responses. While most of this initial learning is behaviorally supported by an expectancy of an aversive outcome and neurally supported by activity within the basolateral amygdala, activity in other brain regions become necessary for the execution of defensive strategies that emerge in other aversive learning paradigms such as active avoidance. Here, we review the neural circuits that support both reactive and proactive defensive behaviors that are motivated by aversive learning, and identify commonalities between the neural substrates of these distinct (and often exclusive) behavioral strategies.

Enhancing fear extinction.

Gradually reducing a source of fear during extinction treatments may weaken negative memories in the long term.

Elevated fear states facilitate ventral hippocampal engagement of basolateral amygdala neuronal activity.

Fear memory formation and retention rely on the activation of distributed neural circuits. The basolateral amygdala (BLA) and ventral hippocampus (VH) in particular are two regions that support contextual fear memory processes and share reciprocal connections. The VH → BLA pathway is critical for increases in fear after initial learning, in both fear renewal following extinction learning and during fear generalization.

Fear extinction is impaired in aged rats.

Normal aging is accompanied by broad loss of cognitive function in humans and rodents, including declines in cognitive flexibility. In extinction, a conditional stimulus (CS) that was previously paired with a footshock is presented alone. This procedure reliably reduces conditional freezing behavior in young adult rats.

Generalization and discrimination of inhibitory avoidance differentially engage anterior and posterior retrosplenial subregions.

Introduction: In a variety of behavioral procedures animals will show selective fear responding in shock-associated contexts, but not in other contexts. However, several factors can lead to generalized fear behavior, where responding is no longer constrained to the conditioning context and will transfer to novel contexts.

Methods: Here, we assessed memory generalization using an inhibitory avoidance paradigm to determine if generalized avoidance behavior engages the retrosplenial cortex (RSC).

Fear Reduced Through Unconditional Stimulus Deflation Is Behaviorally Distinct From Extinction and Differentially Engages the Amygdala.

Background: Context fear memory can be reliably reduced by subsequent pairings of that context with a weaker shock. This procedure shares similarities with extinction learning: both involve extended time in the conditioning chamber following training and reduce context-elicited fear. Unlike extinction, this weak-shock exposure has been hypothesized to engage reconsolidation-like processes that weaken the original memory.

Maturation of a cortical-amygdala circuit limits sociability in male rats.

Prefrontal cortical maturation coincides with adolescent transitions in social engagement, suggesting that it influences social development. The anterior cingulate cortex (ACC) is important for social interaction, including ACC outputs to the basolateral amygdala (BLA). However, little is known about ACC-BLA sensitivity to the social environment and if this changes during maturation.

Memory retrieval, reconsolidation, and extinction: Exploring the boundary conditions of post-conditioning cue exposure.

Following fear conditioning, behavior can be reduced by giving many CS-alone presentations in a process known as extinction or by presenting a few CS-alone presentations and interfering with subsequent memory reconsolidation. While the two share procedural similarities, both the behavioral outcomes and the neurobiological underpinnings are distinct. Here we review the neural and behavioral mechanisms that produce these separate behavioral reductions, as well as some factors that determine whether or not a retrieval-dependent reconsolidation process or an extinction process will be in effect.

The lifetime impact of stress on fear regulation and cortical function.

A variety of stressful experiences can influence the ability to form and subsequently inhibit fear memory. While nonsocial stress can impact fear learning and memory throughout the lifespan, psychosocial stressors that involve negative social experiences or changes to the social environment have a disproportionately high impact during adolescence. Here, we review converging lines of evidence that suggest that development of prefrontal cortical circuitry necessary for both social experiences and fear learning is altered by stress exposure in a way that impacts both social and fear behaviors throughout the lifespan.

Developmental differences in amygdala projection neuron activation associated with isolation-driven changes in social preference.

Adolescence is a developmental period characterized by brain maturation and changes in social engagement. Changes in the social environment influence social behaviors. Memories of social events, including remembering familiar individuals, require social engagement during encoding.

Isolation driven changes in Iba1-positive microglial morphology are associated with social recognition memory in adults and adolescents.

Microglia are critical for regulation of neuronal circuits that mature from adolescence to adulthood. The morphological complexity and process length of microglia can indicate different activation states. These states are sensitive to a variety of environmental and stress conditions.

Contextual control of conditioned pain tolerance and endogenous analgesic systems.

The mechanisms underlying the transition from acute to chronic pain are unclear but may involve the persistence or strengthening of pain memories acquired in part through associative learning. Contextual cues, which comprise the environment in which events occur, were recently described as a critical regulator of pain memory; both male rodents and humans exhibit increased pain sensitivity in environments recently associated with a single painful experience. It is unknown, however, how repeated exposure to an acute painful unconditioned stimulus in a distinct context modifies pain sensitivity or the expectation of pain in that environment.

Examining a role for the retrosplenial cortex in age-related memory impairment.

Aging is often characterized by changes in the ability to form and accurately recall episodic memories, and this is especially evident in neuropsychiatric conditions including Alzheimer's disease and dementia. Memory impairments and cognitive decline associated with aging mirror the impairments observed following damage to the retrosplenial cortex, suggesting that this region might be important for continued cognitive function throughout the lifespan. Here, we review lines of evidence demonstrating that degeneration of the retrosplenial cortex is critically involved in age-related memory impairment and suggest that preservation of function in this region as part of a larger circuit that supports memory maintenance will decrease the deleterious effects of aging on memory processing.

Unique roles for the anterior and posterior retrosplenial cortices in encoding and retrieval of memory for context.

The rat retrosplenial cortex (RSC) makes critical contributions to learning and memory but these contributions may not be uniform along its rostro-caudal axis. Previous work suggests that event-related and context-related information are differentially encoded by anterior and posterior RSC subregions. Here, we further test this idea using a procedure in which spatial/environmental cues (context) and discrete event memories are acquired separately.

Developmental Shifts in Amygdala Activity during a High Social Drive State.

Amygdala abnormalities characterize several psychiatric disorders with prominent social deficits and often emerge during adolescence. The basolateral amygdala (BLA) bidirectionally modulates social behavior and has increased sensitivity during adolescence. We tested how an environmentally-driven social state is regulated by the BLA in adults and adolescent male rats.

Optogenetic inhibition of either the anterior or posterior retrosplenial cortex disrupts retrieval of a trace, but not delay, fear memory.

Previous work investigating the role of the retrosplenial cortex (RSC) in memory formation has demonstrated that its contributions are not uniform throughout the rostro-caudal axis. While the anterior region was necessary for encoding CS information in a trace conditioning procedure, the posterior retrosplenial cortex was needed to encode contextual information. Using the same behavioral procedure, we tested if there was a similar dissociation during memory retrieval.