Pavlovian fear conditioning does not readily occur in rats in naturalistic environments

Pavlovian fear conditioning, which offers the advantage of simplicity in both the control of conditioned and unconditioned stimuli (CS, US) presentation and the analysis of specific conditioned and unconditioned responses (CR, UR) in a controlled laboratory setting, has been the standard model in basic and translational fear research. Despite 100 years of experiments, the utility of fear conditioning has not been trans-situationally validated in real-life contexts. We thus investigated whether fear conditioning readily occurs and guides the animal's future behavior in an ecologically-relevant environment. To do so, Long-Evans rats foraging for food in an open arena were presented with a tone CS paired with electric shock US to their dorsal neck/body that instinctively elicited escape UR to the safe nest. On subsequent test days, the tone-shock paired animals failed to exhibit fear CR to the CS. In contrast, animals that encountered a realistic agent of danger (a looming artificial owl) paired with a shock, simulating a realistic predatory strike, instantly fled to the nest when presented with a tone for the first time. These results illustrate the survival function and precedence of a nonassociative process, rather than associative conditioning, in life-threatening situations that animals are likely to encounter in nature.

Contextual Fear Memory Maintenance Changes Expression of pMAPK, BDNF and IBA-1 in the Pre-limbic Cortex in a Layer-Specific Manner

Post-traumatic stress disorder (PTSD) is a debilitating and chronic fear-based disorder. Pavlovian fear conditioning protocols have long been utilised to manipulate and study these fear-based disorders. Contextual fear conditioning (CFC) is a particular Pavlovian conditioning procedure that pairs fear with a particular context. Studies on the neural mechanisms underlying the development of contextual fear memories have identified the medial prefrontal cortex (mPFC), or more specifically, the pre-limbic cortex (PL) of the mPFC as essential for the expression of contextual fear. Despite this, little research has explored the role of the PL in contextual fear memory maintenance or examined the role of neuronal mitogen-activated protein kinase (pMAPK; ERK 1/2), brain-derived neurotrophic factor (BDNF), and IBA-1 in microglia in the PL as a function of Pavlovian fear conditioning. The current study was designed to evaluate how the maintenance of two different long-term contextual fear memories leads to changes in the number of immune-positive cells for two well-known markers of neural activity (phosphorylation of MAPK and BDNF) and microglia (IBA-1). Therefore, the current experiment is designed to assess the number of immune-positive pMAPK and BDNF cells, microglial number, and morphology in the PL following CFC. Specifically, 2 weeks following conditioning, pMAPK, BDNF, and microglia number and morphology were evaluated using well-validated antibodies and immunohistochemistry (n = 12 rats per group). A standard CFC protocol applied to rats led to increases in pMAPK, BDNF expression and microglia number as compared to control conditions. Rats in the unpaired fear conditioning (UFC) procedure, despite having equivalent levels of fear to context, did not have any change in pMAPK, BDNF expression and microglia number in the PL compared to the control conditions. These data suggest that alterations in the expression of pMAPK, BDNF, and microglia in the PL can occur for up to 2 weeks following CFC. Together the data suggest that MAPK, BDNF, and microglia within the PL of the mPFC may play a role in contextual fear memory maintenance.

Impairment in acquisition of conditioned fear in schizophrenia: a pooled analysis of four studies

Background: Individuals with schizophrenia show impairments in associative learning. One well-studied, quantifiable form of associative learning is Pavlovian fear conditioning. However, to date, studies of fear conditioning in schizophrenia have been inconclusive, possibly because they lacked sufficient power. Methods: To address this issue, data were pooled from 4 independent fear conditioning studies that included a total of 77 individuals with schizophrenia and 74 control subjects. Skin conductance responses (SCRs) during fear conditioning to stimuli that were paired (the CS+) and not paired (CS-) with an aversive, unconditioned stimulus were measured, and the success of acquisition of differential conditioning (the magnitude of CS+ vs CS- SCRs) and responses to CS+ and CS- separately were assessed. Results: Acquisition of differential conditioned fear responses was significantly lower in individuals with schizophreania than in healthy controls (Cohen's d = 0.53). This effect was primarily related to a significantly higher response to the CS- stimulus in the schizophrenia compared to the control group. The magnitude of this response to the CS- in the schizophrenia group was correlated with the severity of delusional ideation. Other symptoms or antipsychotic dose were not associated with fear conditioning measures. Conclusions: Individuals with schizophrenia who endorse delusional beliefs are over-responsive to neutral stimuli during fear conditioning. This finding is consistent with prior models of aberrant learning in psychosis.

Neurotrophin signalling in amygdala-dependent cued fear learning

The amygdala is a central hub for fear learning assessed by Pavlovian fear conditioning. Indeed, the prevailing hypothesis that learning and memory are mediated by changes in synaptic strength was shown most convincingly at thalamic and cortical afferents to the lateral amygdala. The neurotrophin brain-derived neurotrophic factor (BDNF) is known to regulate synaptic plasticity and memory formation in many areas of the mammalian brain including the amygdala, where BDNF signalling via tropomyosin-related kinase B (TrkB) receptors is prominently involved in fear learning. This review updates the current understanding of BDNF/TrkB signalling in the amygdala related to fear learning and extinction. In addition, actions of proBDNF/p75NTR and NGF/TrkA as well as NT-3/TrkC signalling in the amygdala are introduced.