Neural activity in afferent projections to the infralimbic cortex is associated with individual differences in the recall of fear extinction.

Post-traumatic stress disorder (PTSD) is characterized by an impaired ability to extinguish fear responses to trauma-associated cues. Studies in humans and non-human animals point to differences in the engagement of certain frontal cortical regions as key mediators determining whether or not fear extinction is successful, however the neural circuit interactions that dictate the differential involvement of these regions are not well understood. To better understand how individual differences in extinction recall are reflected in differences in neural circuit activity, we labeled projections to the infralimbic cortex (IL) in rats using a retrograde tracer and compared neural activity within, and outside, of IL-projecting neurons. We analyzed these data in groups separated on the basis of how well rats retained extinction memory. We found that within IL-projecting cells, neurons in the posterior paraventricular thalamus showed heightened activity in rats that showed good extinction recall. Outside of the IL-projecting cells, increased Fos activity was observed in good extinction rats in select regions of the claustrum and ventral hippocampus. Our results indicate that differences in extinction recall are associated with a specific pattern of neural activity both within and outside of projections to the IL.

Behavioral Expression of Contextual Fear in Male and Female Rats.

The study of fear conditioning has led to a better understanding of fear and anxiety-based disorders such as post-traumatic stress disorder (PTSD). Despite the fact many of these disorders are more common in women than in men, the vast majority of work investigating fear conditioning in rodents has been conducted in males. The goal of the work presented here was to better understand how biological sex affects contextual fear conditioning and expression. To this end, rats of both sexes were trained to fear a specific context and fear responses were measured upon re-exposure to the conditioning context. In the first experiment, male and female rats were given context fear conditioning and tested the next day during which freezing behavior was measured. In the second experiment, rats were trained and tested in a similar fashion while fear-potentiated startle and defecation were measured. We found that males showed more freezing behavior than females during a fear expression test. The expression of fear-potentiated startle did not differ between sexes, while males exhibited more defecation during a test in a novel context. These data suggest that the expression of defensive behavior differs between sexes and highlight the importance of using multiple measures of fear when comparing between sexes.

Individual variability in the recall of fear extinction is associated with phosphorylation of mitogen-activated protein kinase in the infralimbic cortex.

RATIONALE: Although most individuals will be exposed to trauma at some point, only a small portion of individuals develops posttraumatic stress disorder (PTSD), suggesting there are factors which render some individuals particularly susceptible to the development of this disorder. One cardinal feature of PTSD is the failure to extinguish fear responses to cues that once signaled danger. Rodent studies of fear learning and extinction have provided insight into the neural mechanisms underlying extinction; however, most of these studies have focused on mechanisms involved in typical responses and fewer have identified mechanisms that distinguish animals that extinguish well versus those that do not extinguish their fear responses. Investigation of individual differences in fear extinction might help us better understand the susceptibility to and development of PTSD. OBJECTIVES: In order to understand the neural mechanisms underlying such variation, we assessed phosphorylated mitogen-activated protein kinase (P-MAPK) levels in infralimbic cortex (IL), basolateral amygdala (BLA), and dorsal hippocampus in subsets of rats which exhibited good or poor recall of extinction. RESULTS: We found a relationship between extinction recall and P-MAPK in the IL such that rats which had good extinction recall had higher levels of P-MAPK than those which had poor extinction recall. We also found that rats which had good extinction recall had higher levels of P-MAPK in the dorsal hippocampus than control rats. CONCLUSIONS: Our findings suggest that individual differences in the recall of extinction learning can be explained by altered cell signaling in the IL.

Facilitation of fear learning by prior and subsequent fear conditioning.

Classical fear conditioning is perhaps the premier model system used to study the neurobiological basis of memory formation. Prior work has resulted in a good understanding of both the molecular mechanisms and neural circuits supporting this form of learning. However, much of what is known about these mechanisms comes from studies in which fear memory is acquired using a single, isolated training session. Given that we cannot divorce the acquisition of new information from the backdrop on which it occurs, studies are needed to determine how the acquisition of fear memory is affected by other learning events. Here, we used rats to describe the time course by which auditory fear conditioning can facilitate learning to a different fear learning event, which alone is insufficient to support long-term fear memory. First, we replicated previous findings showing that although a single trial of light and shock produces little evidence of memory, two identical trials spaced 60 min or 24 h apart support long-term memory. Next, we report that a typical auditory fear conditioning session facilitated memory formation when rats were subsequently exposed to a single trial of light and shock 60 min or 24 h, but not 4 min, later. Finally, we show that learning can be enhanced retroactively if auditory fear conditioning occurs 60 min, but not 24 h, after a single light-shock pairing. These data demonstrate that a weak fear conditioning trial can be enhanced by prior and subsequent fear conditioning depending on the timing between training events.

Acoustic startle response in rats predicts inter-individual variation in fear extinction.

Although a large portion of the population is exposed to a traumatic event at some point, only a small percentage of the population develops post-traumatic stress disorder (PTSD), suggesting the presence of predisposing factors. Abnormal acoustic startle response (ASR) has been shown to be associated with PTSD, implicating it as a potential predictor of the development of PTSD-like behavior. Since poor extinction and retention of extinction learning are characteristic of PTSD patients, it is of interest to determine if abnormal ASR is predictive of development of such deficits. To determine whether baseline ASR has utility in predicting the development of PTSD-like behavior, the relationship between baseline ASR and freezing behavior following Pavlovian fear conditioning was examined in a group of adult, male Sprague-Dawley rats. Baseline acoustic startle response (ASR) was assessed preceding exposure to a Pavlovian fear conditioning paradigm where freezing behavior was measured during fear conditioning, extinction training, and extinction testing. Although there was no relationship between baseline ASR and fear memory following conditioning, rats with low baseline ASR had significantly lower magnitude of retention of the extinction memory than rats with high baseline ASR. The results suggest that baseline ASR has value as a predictive index of the development of a PTSD-like phenotype.

Proteolytic regulation of synaptic plasticity in the mouse primary visual cortex: analysis of matrix metalloproteinase 9 deficient mice.

The extracellular matrix (ECM) is known to play important roles in regulating neuronal recovery from injury. The ECM can also impact physiological synaptic plasticity, although this process is less well understood. To understand the impact of the ECM on synaptic function and remodeling in vivo, we examined ECM composition and proteolysis in a well-established model of experience-dependent plasticity in the visual cortex. We describe a rapid change in ECM protein composition during Ocular Dominance Plasticity (ODP) in adolescent mice, and a loss of ECM remodeling in mice that lack the extracellular protease, matrix metalloproteinase-9 (MMP9). Loss of MMP9 also attenuated functional ODP following monocular deprivation (MD) and reduced excitatory synapse density and spine density in sensory cortex. While we observed no change in the morphology of existing dendritic spines, spine dynamics were altered, and MMP9 knock-out (KO) mice showed increased turnover of dendritic spines over a period of 2 days. We also analyzed the effects of MMP9 loss on microglia, as these cells are involved in extracellular remodeling and have been recently shown to be important for synaptic plasticity. MMP9 KO mice exhibited very limited changes in microglial morphology. Ultrastructural analysis, however, showed that the extracellular space surrounding microglia was increased, with concomitant increases in microglial inclusions, suggesting possible changes in microglial function in the absence of MMP9. Taken together, our results show that MMP9 contributes to ECM degradation, synaptic dynamics and sensory-evoked plasticity in the mouse visual cortex.