Stress-induced preproenkephalin mRNA expression in the amygdala changes during early ontogeny in the rat.

Stress activates endogenous opioids that modulate nociceptive transmission. Exposure to a potentially infanticidal adult male rat suppresses pain-related behaviors in pre-weaning but not in older rats. This male-induced analgesia is mediated by l opioid receptors in the periaqueductal gray, a midbrain structure that is innervated by amygdala projections. To determine whether enkephalin, a l and d opioid receptor agonist, is activated by male exposure, mRNA levels of its precursor, preproenkephalin, were measured in subdivisions of the amygdala and the periaqueductal gray. In 14-day-old but not in 21-day-old rats, 5 min of male exposure induced analgesia to heat and increased preproenkephalin mRNA levels in the central nucleus of the amygdala but not in the periaqueductal gray. The change in the activation of enkephalinergic neurons in the central amygdala may contribute to the change in stress-induced analgesia during early ontogeny.

Developmental changes in c-fos expression to an age-specific social stressor in infant rats.

Young rats become immobile when exposed to a potentially infanticidal adult male rat. Male-induced immobility declines during the preweaning period, paralleling the decrease in infanticidal threat. To investigate the neural substrates underlying the developmental change in immobility, male-induced expression of the immediate-early gene c-fos was assessed on postnatal days 7, 14 and 21. A huddle of three young rats was exposed to an adult male behind a screen. As control, three littermates were put in the testing chamber but not exposed to the male. On day 7, male exposed and control pups were immobile most of the time and c-fos expression did not differ between conditions. On day 14, rats in the presence of the male stopped ongoing behaviors and became immobile. They had significantly higher c-fos expression in the paraventricular nucleus of the hypothalamus, the amygdala, the periaqueductal gray, and the locus ceruleus. On day 21, the male-exposed rats that were immobile had elevated c-fos expression in a similar pattern as on day 14, however, different nuclei of the amygdala were activated. In contrast, male-exposed 21-day-old rats that showed control levels of immobility did not have elevated c-fos expression in these areas. These results demonstrate that male exposure induced c-fos expression in brain areas of young rats in an age-specific pattern. Some of the activated brain areas seem to have contributed to immobility. Differential activation of neuronal populations may underlie developmental changes in defensive immobility during early ontogeny.

Developmental changes in responsivity to threat are stimulus-specific in rats.

During early ontogeny, stimuli that pose a threat to an animal change. Unrelated adult male rats may kill young rats, but infanticide ends around weaning. Predation, on the other hand, may increase during early ontogeny when rats begin to extend their activity range. We investigated the developmental course of two defensive responses, immobility and analgesia, in young rats exposed to an adult male rat or to predator cues. Preweaning 14-day-old rats became immobile and analgesic when exposed to the male and showed immobility but not analgesia when exposed to cat odor. On Day 26, around weaning, the presence of the male rat no longer induced immobility and analgesia whereas cat odor produced higher levels of immobility and analgesia compared to control and male-exposed animals. This developmental change in responsivity may reflect the differences in the risk of being harmed by a male or a cat during different periods of ontogeny.

Olfactory based spatial learning in neonatal mice and its dependence on CaMKII.

Spatial learning and memory involves the ability to encode geometric relationships between perceived cues and depends critically on the hippocampus. Visually guided spatial learning has been demonstrated in adult animals. As infant animals rely heavily on olfaction, olfactory based spatial learning was assessed in infant mice. When 12-day-old pups were displaced from their nest, they learned within a few training trials to use the spatial pattern of odor cues to move back to the nest. However, mouse pups that over-expressed Ca2+/calmodulin-dependent protein kinase (CaMKII) in hippocampal neurons were impaired in olfactory based spatial learning.

The effect of periaqueductal gray lesions on responses to age-specific threats in infant rats.

During early ontogeny infant rats show specific responses to a variety of age-dependent threatening situations. When isolated from nest and dam, they emit ultrasonic vocalizations and show decreased reactivity to noxious stimulation, or analgesia. When exposed to an unfamiliar adult male, they become immobile and analgesic. The midbrain periaqueductal gray (PAG) is an important area within the circuitry that controls responses to threatening stimuli in the adult. Little is known about the functions of the PAG in early life. It was hypothesized that the PAG mediates the responses to the age-specific threats social isolation and male exposure in the infant rat. Rat pups were lesioned electrolytically either in the lateral or the ventrolateral PAG on postnatal day 7, tested in social isolation on day 10, and exposed to a male on day 14. On day 10 during isolation, ultrasonic vocalizations and isolation-induced analgesia were decreased in both lesion groups. On day 14, male-induced immobility and analgesia were decreased in ventrally lesioned animals. In conclusion, the PAG seems to play a developmentally continuous role in age-specific responses to threat such as ultrasonic vocalization, analgesia, and immobility.

Mu opioid receptors in the ventrolateral periaqueductal gray mediate stress-induced analgesia but not immobility in rat pups.

Rat pups become immobile and analgesic when exposed to an adult male rat. The aim of this study was to determine whether these reactions are under the control of endogenous opioids and to determine the role of the midbrain periaqueductal gray (PAG), which mediates stress-induced immobility and analgesia in adult animals. In Experiment 1, 14-day-old rats were injected systemically with the general opioid receptor antagonist naltrexone (1 mg/kg), which blocked male-induced analgesia to thermal stimulation but did not affect immobility. In Experiment 2, the selective mu opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP; 50 or 100 ng/200 nl) was microinjected into the ventrolateral and lateral PAG. CTOP suppressed male-induced analgesia when injected into the ventrolateral PAG. Male-induced immobility was not affected by CTOP. Male proximity therefore seems to induce analgesia in rat pups by releasing endogenous opioids that bind to mu opioid receptors in the ventrolateral PAG.

Ontogeny of defensive behavior and analgesia in rat pups exposed to an adult male rat.

Aversive situations may reduce nociception. The mechanism underlying such analgesia has been suggested to involve the interaction between the two separate but interconnected motivational systems "defense" and "pain." To determine the developmental course of defense and nociception, these processes were analyzed during early ontogeny in rats. To elicit a defensive reaction, a huddle of preweanling rat pups was exposed to an unfamiliar, unrelated adult male, or, for comparison, to the mother. On postnatal Day 7 the pups did not show a behavioral reaction to the presence of the mother or the male, and no reduction in nociceptive threshold in a thermal paw withdrawal test. On Day 14, pups in the presence of the male stopped ongoing behaviors and became immobile, and showed reduced paw withdrawal after the exposure. At Day 21, 22 pups of 32 became immobile when exposed to the male, whereas 10 pups explored the partition separating them from the male. Neither group showed reduced paw withdrawal. Immobility was considered a defensive reaction because it reduces auditory and visual cues and therefore the probability of being detected. The developmental course of immobility seems to reflect both the changes in threat imposed on the pups by a potentially infanticidal male and the ability of pups to react to that threat. The reduction in paw withdrawal that followed male exposure indicates an inhibitory mechanism. It is discussed whether the activation of the defense system results in an inhibition of nociception.