The role of hippocampal spatial representations in contextualization and generalization of fear.

Using contextual information to predict aversive events is a critical ability that protects from generalizing fear responses to safe contexts. Animal models have demonstrated the importance of spatial context representations within the hippocampal formation in contextualization of fear learning. The ventromedial prefrontal cortex (vmPFC) is known to play an important role in safety learning, possibly also through the incorporation of context information. However, if contextual representations are related to context-dependent expression of fear memory in humans remains unclear. Twenty-one healthy participants underwent functional MRI combined with a cue-context conditioning paradigm within a self-navigated virtual reality environment. The environment included two buildings (Threat and Safe context), which had distinct features outside but were identical inside. Within each context, participants saw two cues (CS+, CS-). The CS+ was consistently (100% reinforcement rate) paired with an electric shock in the Threat context, but never in the Safe context. The CS- was never paired with a shock. We found robust differential skin conductance responses (SCRs; CS+ â€‹> â€‹CS-) in the Threat context, but also within the Safe context, indicating fear generalization. Within the Safe context, vmPFC responses to the CS+ were larger than those in the Threat context. We furthermore found environment-specific representations for the two contexts in the training paradigm (i.e., before conditioning took place) in the hippocampus to be related to fear expression and generalization. Namely, participants with a weak context representation (z-score < 1.65) showed stronger fear generalization compared to participants with a strong context representation (z-score > 1.65). Thus, a weak neural representation strength of spatial context may explain overgeneralization of memory to safe contexts. In addition, our findings demonstrate that context-dependent regulation of fear expression engages ventromedial prefrontal pathways suggesting this involves a similar mechanism that is known to be involved in retrieval of extinction memory.

Perinatal reduction of functional serotonin transporters results in developmental delay.

While there is strong evidence from rodent and human studies that a reduction in serotonin transporter (5-HTT) function in early-life can increase the risk for several neuropsychiatric disorders in adulthood, the effects of reduced 5-HTT function on behavior across developmental stages are underinvestigated. To elucidate how perinatal pharmacological and lifelong genetic inactivation of the 5-HTT affects behavior across development, we conducted a battery of behavioral tests in rats perinatally exposed to fluoxetine or vehicle and in 5-HTT(-/-) versus 5-HTT(+/+) rats. We measured motor-related behavior, olfactory function, grooming behavior, sensorimotor gating, object directed behavior and novel object recognition in the first three postnatal weeks and if possible the tests were repeated in adolescence and adulthood. We also measured developmental milestones such as eye opening, reflex development and body weight. We observed that both pharmacological and genetic inactivation of 5-HTT resulted in a developmental delay. Except for hypo-locomotion, most of the observed early-life effects were normalized later in life. In adolescence and adulthood we observed object directed behavior and decreased novel object recognition in the 5-HTT(-/-) rats, which might be related to the lifelong inactivation of 5-HTT. Together, these data provide an important contribution to the understanding of the effects of perinatal and lifelong 5-HTT inactivation on behavior across developmental stages.