The earliest stages of development are critically sensitive to environmental insults. An unfortunately timed stress on the developing brain can have dramatic consequences for the neurodevelopment and future mental health of the individual. In particular, infection of the mother during pregnancy has been correlated with increased risk of psychiatric and neurodevelopmental disorders. Evidence suggests that maternal immune activation, independently from the infection itself, can be responsible for the outcome in the offspring. This recognition has resulted in expanding study designs from epidemiologic correlations to the search for a causal relationship between activation of the maternal immune system and cognitive consequences for the offspring. However, this causality analysis remained limited in humans until recent work that longitudinally linked specific markers of maternal inflammation during pregnancy with alterations of the newborn brain and cognitive development of toddlers. This focused narrative review compares and discusses the results of these recent studies and places them into the broader landscape of maternal immune activation literature. New data point, in particular, to the association between the levels of interleukin 6 (IL-6) and modifications of the offspring’s salience network and subsequent cognitive impairments. This article further emphasizes the need to carefully control for potential confounders in studying the effects of maternal immune activation on the neonatal brain as well as the under-investigated consequences of intra-partum fever on offspring neurodevelopment.

Throughout life, rats emit ultrasonic vocalizations (USV) when confronted with an aversive situation. However, the conditions classically used to elicit USV vary greatly with the animal’s age (isolation from the dam in infancy, versus nociceptive stimulation in adults). The present study is the first to characterize USV responses to the same aversive event throughout development. Specifically, infant, juvenile and adult rats were presented with mild foot-shocks and their USV frequency, duration, and relationship with respiration and behavior were compared. In juvenile and adult rats, a single class of USV is observed with an age-dependent main frequency and duration (30 kHz/400 ms in juveniles, 22 kHz/900 ms in adults). In contrast, infant rat USV were split into two classes with specific relationships with respiration and behavior: 40 kHz/300 ms and 66 kHz/21 ms. Next, we questioned if these infant USV were also emitted in a more naturalistic context by exposing pups to interactions with the mother treating them roughly. This treatment enhanced 40-kHz USV while leaving 66-kHz USV unchanged suggesting that the use of USV goes far beyond a signal studied in terms of amount of emission, and can inform us about some aspects of the infant’s affective state.

Pavlovian aversive conditioning requires learning of the association between a conditioned stimulus (CS) and an unconditioned, aversive stimulus (US) but also involves encoding the time interval between the two stimuli. The neurobiological bases of this time interval learning are unknown. Here, we show that in rats, the dorsal striatum and basal amygdala belong to a common functional network underlying temporal expectancy and learning of a CS–US interval. Importantly, changes in coherence between striatum and amygdala local field potentials (LFPs) were found to couple these structures during interval estimation within the lower range of the theta rhythm (3–6 Hz). Strikingly, we also show that a change to the CS–US time interval results in long-term changes in cortico-striatal synaptic efficacy under the control of the amygdala. Collectively, this study reveals physiological correlates of plasticity mechanisms of interval timing that take place in the striatum and are regulated by the amygdala.

Interval timing refers to the ability to perceive, estimate and discriminate durations in the range of seconds to minutes. Very little is currently known about the ontogeny of interval timing throughout development. On the other hand, even though the neural circuit sustaining interval timing is a matter of debate, the striatum has been suggested to be an important component of the system and its maturation occurs around the third post-natal (PN) week in rats. The global aim of the present study was to investigate interval timing abilities at an age for which striatum is not yet mature. We used odor fear conditioning, as it can be applied to very young animals. In odor fear conditioning, an odor is presented to the animal and a mild footshock is delivered after a fixed interval. Adult rats have been shown to learn the temporal relationships between the odor and the shock after a few associations. The first aim of the present study was to assess the activity of the striatum during odor fear conditioning using 2-Deoxyglucose autoradiography during development in rats. The data showed that although fear learning was displayed at all tested ages, activation of the striatum was observed in adults but not in juvenile animals. Next, we assessed the presence of evidence of interval timing in ages before and after the inclusion of the striatum into the fear conditioning circuit. We used an experimental setup allowing the simultaneous recording of freezing and respiration that have been demonstrated to be sensitive to interval timing in adult rats. This enabled the detection of duration-related temporal patterns for freezing and/or respiration curves in infants as young as 12 days PN during odor fear conditioning. This suggests that infants are able to encode time durations as well as and as quickly as adults while their striatum is not yet functional. Alternative networks possibly sustaining interval timing in infant rats are discussed.

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Fear behavior depends on interactions between the medial prefrontal cortex (mPFC) and the basolateral amygdala (BLA), and the expression of fear involves synchronized activity in theta and gamma oscillatory activities. In addition, freezing, the most classical measure of fear response in rodents, temporally coincides with the development of sustained 4-Hz oscillations in prefrontalamygdala circuits. Interestingly, these oscillations were recently shown to depend on the animal's respiratory rhythm, supporting the growing body of evidence pinpointing the influence of nasal breathing on brain rhythms. During fearful states, rats also emit 22-kHz ultrasonic vocalizations (USV) which drastically affect respiratory rhythm. However, the relationship between 22-kHz USV, respiration and brain oscillatory activities is still unknown. Yet such information is crucial for a comprehensive understanding of how the different components of fear response collectively modulate rat's brain neural dynamics. Here we trained male rats in an odor fear conditioning task, while recording simultaneously local field potentials in BLA, mPFC and olfactory piriform cortex, together with USV calls and respiration. We show that USV calls coincide with an increase in delta and gamma power and a decrease in theta power. In addition, during USV emission in contrast to silent freezing, there is no coupling between respiratory rate and delta frequency, and the modulation of fast oscillations amplitude relative to the phase of respiration is modified. We propose that sequences of USV calls could result in a differential gating of information within the network of structures sustaining fear behavior, thus potentially modulating fear expression/memory. Significance StatementWhile freezing is the most frequently used measure of fear, it is only one amongst the different components of rodents' response to threatening events. USV is another index that gives additional insight into the socioemotional status of an individual. Our study is the first to describe the effects of USV production on rat's brain oscillatory activities in the fear neural network, and to relate some of them to changes in nasal breathing. A better knowledge of the impact of USV calls on brain neural dynamics is not only important for understanding the respective weight of the different components of fear response, but is also particularly relevant for rodent models of human neuropsychiatric disorders, for which socio-affective communication is severely impaired.

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