The Role of the Medial Prefrontal Cortex in Innate Fear Regulation in Infants, Juveniles, and Adolescents

Abstract

In adult animals, the medial prefrontal cortex (mPFC) plays a significant role in regulating emotions and projects to the amygdala and periaqueductal gray (PAG) to modulate emotional responses. However, little is known about the development of this neural circuit and its relevance to unlearned fear in pre-adulthood. To address these issues, we examined the mPFC of 14 (infants), 26 (juveniles), and 38–42 (adolescents) day old rats, to represent different developmental and social milestones. The expression patterns of the neuronal marker FOS were used to assess neurological activity. Muscimol, a GABA agonist, was used to inactivate the prelimbic and infralimbic mPFC subdivisions (400 ng in 200 nl). Animals were exposed to either a threatening or non-threatening stimulus that was ecologically relevant and age-specific. Freezing was measured as an indicator of innate fear behavior. The data indicated that the mPFC is neither active nor responsive to innate fear in infant rats. In juveniles, the prelimbic mPFC became responsive in processing aversive sensory stimulation, but did not regulate freezing behavior. Finally, during adolescence, inactivation of the prelimbic mPFC significantly attenuated freezing, and decreased FOS expression in the ventral PAG. Surprisingly, across all ages, there were no significant differences in FOS levels in the medial and basolateral/lateral amygdala when either mPFC subdivision was inactivated. Taken together, unlearned fear has a unique developmental course with different brain areas involved in unlearned fear in the immature animal than the adult. In particular, the mPFC neural circuitry is different in young animals and progressively develops more capacities as the animal matures.

GABAA Receptors Predict Aversion-Related Brain Responses: An fMRI-PET Investigation in Healthy Humans

“…These studies have contributed greatly to an understanding of aversive learning mechanisms at the microcircuit level and, indeed, congruent findings have been noted at the macroscopic level in humans (Delgado et al, 2011). The role of the prefrontal cortex in response to threatening stimuli has also been noted in rodents (Chan et al, 2011;Thompson et al, 2010), and there is evidence that context-dependent aversion-related activity may involve GABAergic function (Fiorelli et al, 2008;Lehner et al, 2010).…”

Medial Prefrontal Cortex Processes Threatening Stimuli in Juvenile Rats

“…We tested juveniles together to minimize the stress of isolation since the animals were group-housed. Experiments were conducted as detailed previously (Chan et al, 2011). Briefly, they were placed in the testing cage (46 Â 25 Â 21 cm) that was subdivided by a wire-mesh partition positioned in the middle of the cage, forming two equal compartments.…”

“…By postnatal day (PN)13, neurons in all subdivisions of the mPFC project to the amygdala and the density of projections increases with age (Bouwmeester et al, 2002). In preweaning pups (PN14), the mPFC is not activated by threats (Chan et al, 2011). In adolescent animals (PN38-42), the mPFC is activated and influences freezing (Chan et al, 2011).…”

“…In preweaning pups (PN14), the mPFC is not activated by threats (Chan et al, 2011). In adolescent animals (PN38-42), the mPFC is activated and influences freezing (Chan et al, 2011). In contrast, the postweaning juvenile period (PN26) appears to be a critical intermediate time because exposure to a threatening stimulus produces robust freezing behavior and activates the fear circuit yet is unaltered by inactivation of the mPFC (Chan et al, 2011).…”

“…In adolescent animals (PN38-42), the mPFC is activated and influences freezing (Chan et al, 2011). In contrast, the postweaning juvenile period (PN26) appears to be a critical intermediate time because exposure to a threatening stimulus produces robust freezing behavior and activates the fear circuit yet is unaltered by inactivation of the mPFC (Chan et al, 2011). Thus, at this age, the mPFC is 'aware' of the threat but does not respond to it as it does in adults.…”