Early environmental regulation of neural systems mediating fearfulness

Postnatal handling of rat litters during the first week of life greatly decreases behavioural fearfulness to novelty in the adult offspring. Our first question was to what extent the Benzodiazepine/GABAA receptor complex, a system critical for the expression of fear, might be involved in mediating the observed reduced fearfulness in handled animals (H). Benzodiazepine receptor (BZ) binding was reduced in the amygdala and locus coeruleus (LC), regions important for the expression of fear in non-handled (NH) and maternally separated animals (MS). Moreover, levels of the mRNA for the gamma2 sub-unit of the GABAA receptor complex, which confers high affinity BZ binding, were higher in the amygdaloid nuclei as well as in the LC of handled compared with both NH and MS animals.Studies with the handling paradigm have lead to the idea that variations mother-pup interactions may actually be the cause of the handling effects. As adults, the offspring of mothers which exhibited high levels of licking/grooming and arched-back nursing (LG-ABN) showed substantially reduced behavioral fearfulness in response to novelty compared to the offspring of low LG-ABN mothers. In addition, the adult offspring of the high and low LGABN mothers showed the same receptor and molecular profiles as H and NH adult offspring. Corticotropin releasing factor (CRF) and alpha2 norepinephrine receptor levels, additional receptor systems thought to be important in the expression of fearfulness, differed in these animals too. Adoption studies give further support to the maternal hypothesis in the finding that the expression mRNA for the gamma2 sub-unit of the GABAA receptor complex can be differentially expressed as a result of different offspring to mother combinations.Taken together, these findings suggest that early life events (ie: naturally occurring differences in maternal care) during the first few days of life have long-term effects on the development of central neurotransmitter systems, which mediate the expression of fearfulness to novelty