The Human Affectome.

Over the last decades, theoretical perspectives in the interdisciplinary field of the affective sciences have proliferated rather than converged due to differing assumptions about what human affective phenomena are and how they work. These metaphysical and mechanistic assumptions, shaped by academic context and values, have dictated affective constructs and operationalizations. However, an assumption about the purpose of affective phenomena can guide us to a common set of metaphysical and mechanistic assumptions. In this capstone paper, we home in on a nested teleological principle for human affective phenomena in order to synthesize metaphysical and mechanistic assumptions. Under this framework, human affective phenomena can collectively be considered algorithms that either adjust based on the human comfort zone (affective concerns) or monitor those adaptive processes (affective features). This teleologically-grounded framework offers a principled agenda and launchpad for both organizing existing perspectives and generating new ones. Ultimately, we hope the Human Affectome brings us a step closer to not only an integrated understanding of human affective phenomena, but an integrated field for affective research.

Amplitude modulation pattern of rat distress vocalisations during fear conditioning.

In humans, screams have strong amplitude modulations (AM) at 30 to 150 Hz. These AM correspond to the acoustic correlate of perceptual roughness. In bats, distress calls can carry AMs, which elicit heart rate increases in playback experiments. Whether amplitude modulation occurs in fearful vocalisations of other animal species beyond humans and bats remains unknown. Here we analysed the AM pattern of rats' 22-kHz ultrasonic vocalisations emitted in a fear conditioning task. We found that the number of vocalisations decreases during the presentation of conditioned stimuli. We also observed that AMs do occur in rat 22-kHz vocalisations. AMs are stronger during the presentation of conditioned stimuli, and during escape behaviour compared to freezing. Our results suggest that the presence of AMs in vocalisations emitted could reflect the animal's internal state of fear related to avoidance behaviour.

Respiratory response to an odor throughout development in rats.

Odor-induced sniffing has proven to be a useful behavioral readout for assessing olfactory performance in adult rats. However, little is known about how the respiratory response changes throughout ontogeny. Thus, this study aimed at characterizing respiratory response to an odor in rats using paradigms suitable to infants, juveniles, and adults. We first analyzed the respiratory response to a neutral, novel odor. Then the value of the odor was changed either through its repeated presentation (odor habituation), or its association with a foot-shock (odor fear). In the habituation task, we found that the first presentation of the novel odor induced a clear sniffing response at all 3 ages, but the peak respiratory frequency was higher in adults than in juveniles and infants. When the odor was presented repeatedly, the sniffing response gradually faded and the younger the animal, the faster the fading of the response. In the fear conditioning task, the odor induced an increase in respiratory rate that persisted until the end of the session in adults and infants, but not in juveniles. In another group for which the odor was explicitly unpaired with the foot-shock, the respiratory response to the odor did not last as long over the session than in the paired condition at all 3 ages. Finally, we observed that shock delivery induced a similar respiratory response at the 3 investigated ages in the paired and unpaired conditions. Collectively, these data show that the respiratory response constitutes a faithful index to assess rat's olfactory abilities throughout ontogeny.

A structured professional development curriculum for postdoctoral fellows leads to recognized knowledge growth.

Postdoctoral training enables research independence and professional readiness. National reports have emphasized professional development as a critical component of this training period. In response, many institutions are establishing transferable skills training workshops for postdocs; however, the lack of structured programs and an absence of methods to assess outcomes beyond participant satisfaction surveys are critical gaps in postdoctoral training. To address these shortcomings, we took the approach of structured programming and developed a method for controlled assessment of outcomes. Our program You3 (You, Your Team, Your Project), co-designed by postdoctoral fellows, focused on discussing specific management and leadership skills agnostic of ultimate career path(s) in a structured manner. We then measured outcomes in a controlled manner, by systematically comparing perceived knowledge and growth as indicators of awareness and confidence in participants against that of non-participants as the control group. You3 participants self-rated greater growth in targeted competencies compared to non-participants independent of the number of years of training. This growth was shown by multiple criteria including self-reporting and associative analysis. Correspondingly, You3 participants reported greater knowledge in 75% of the modules when compared to controls. These data indicate that structured learning, where postdocs commit to a curriculum via a cohort-structure, leads to positive outcomes and provides a framework for programs to assess outcomes in a rigorous manner.

Ultrasonic Vocalizations Emission across Development in Rats: Coordination with Respiration and Impact on Brain Neural Dynamics.

Rats communicate using ultrasonic vocalizations (USV) throughout their life when confronted with emotionally stimulating situations, either negative or positive. The context of USV emission and the psychoacoustic characteristics of the vocalizations change greatly between infancy and adulthood. Importantly, the production of USV is tightly coordinated with respiration, and respiratory rhythm is known to influence brain activity and cognitive functions. This review goes through the acoustic characteristics and mechanisms of production of USV both in infant and adult rats and emphasizes the tight relationships that exist between USV emission and respiration throughout the rat's development. It further describes how USV emission and respiration collectively affect brain oscillatory activities. We discuss the possible association of USV emission with emotional memory processes and point out several avenues of research on USV that are currently overlooked and could fill gaps in our knowledge.

Dorsal striatum and the temporal expectancy of an aversive event in Pavlovian odor fear learning.

Interval timing, the ability to encode and retrieve the memory of intervals from seconds to minutes, guides fundamental animal behaviors across the phylogenetic tree. In Pavlovian fear conditioning, an initially neutral stimulus (conditioned stimulus, CS) predicts the arrival of an aversive unconditioned stimulus (US, generally a mild foot-shock) at a fixed time interval. Although some studies showed that temporal relations between CS and US events are learned from the outset of conditioning, the question of the memory of time and its underlying neural network in fear conditioning is still poorly understood. The aim of the present study was to investigate the role of the dorsal striatum in timing intervals in odor fear conditioning in male rats. To assess the animal's interval timing ability in this paradigm, we used the respiratory frequency. This enabled us to detect the emergence of temporal patterns related to the odor-shock time interval from the early stage of learning, confirming that rats are able to encode the odor-shock time interval after few training trials. We carried out reversible inactivation of the dorsal striatum before the acquisition session and before a shift in the learned time interval, and measured the effects of this treatment on the temporal pattern of the respiratory rate. In addition, using intracerebral microdialysis, we monitored extracellular dopamine level in the dorsal striatum throughout odor-shock conditioning and in response to a shift of the odor-shock time interval. Contrary to our initial predictions based on the existing literature on interval timing, we found evidence suggesting that transient inactivation of the dorsal striatum may favor a more precocious buildup of the respiratory frequency's temporal pattern during the odor-shock interval in a manner that reflected the duration of the interval. Our data further suggest that the conditioning and the learning of a novel time interval were associated with a decrease in dopamine level in the dorsal striatum, but not in the nucleus accumbens. These findings prompt a reassessment of the role of the striatum and striatal dopamine in interval timing, at least when considering Pavlovian aversive conditioning.

Maternal Noninfectious Fever Enhances Cell Proliferation and Microglial Activation in the Neonatal Rat Dentate Gyrus.

BACKGROUND: Fever and increased maternal interleukin-6 (IL-6) plasma levels in labor are associated with an increased risk of adverse events in offspring, including neonatal seizures, cerebral palsy, and low intelligence scores at school age. However, the neural changes in the neonate that might mediate the adverse effects of maternal noninfectious fever are not fully characterized. This study was designed to test the hypothesis that induced maternal noninfectious fever alters neonatal neural progenitor cell proliferation and enhances microglial activation in the rat dentate gyrus of the hippocampus. METHODS: Systemic vehicle or IL-6 was given 3 times to near-term pregnant rats (n = 7/group) every 90 minutes, and maternal core temperature was recorded. Neonatal brains were processed and analyzed for dentate gyrus cell proliferation (using Ki-67, n = 10/group, and glial fibrillary acidic protein, n = 6/group) and resident microglia activation (using ionized calcium-binding adaptor protein-1 [Iba-1], n = 6/group). In separate studies, the authors assessed microglia proliferation using Ki-67/Iba-1 costaining (n = 5/group). RESULTS: Compared to controls, exposure to IL-6 resulted in significant maternal temperature increase [mean temperature difference 0.558°C (95% CI, 0.417-0.698; P < .0001)]. Following maternal IL-6, Ki-67 cell proliferation in the dentate gyrus was 55 % higher in neonates whose mother received IL-6 (38.8 ± 9.2) compared with those that received vehicle (25.1 ± 7.8); mean difference 13.7 (95% CI, 5.68-21.71); (P = .0021). Glial fibrillary acidic protein cell proliferation was 40% higher in the neonatal dentate gyrus whose mother received IL-6 when compared to controls (713 ± 85.52 vs 500 ± 115); mean difference 212 (95% CI, 82.2-343.4); (P = .004). Resident microglial activation was 90% higher in the dentate gyrus of neonates whose mother received IL-6 when compared to controls (71.8 ± 9.3 vs 37.8 ± 5.95); mean Iba-1 in stained cells was significantly different between IL-6 and vehicle groups 34 (95% CI, 23.94-44.05); (P < .0001). Proliferating microglia, determined by the colocalization of Ki-67 and Iba-1, were not different in the vehicle (8.8 % ± 3.19 %) and the IL-6 (5.6% ± 2.3%) groups (mean difference 3.2% (95% CI, -0.8-7.25) (P = .1063). CONCLUSIONS: IL-6 is sufficient to induce maternal systemic temperature increases in near-term pregnant rats as well as neuronal, glial, and neuroinflammatory changes in the dentate gyrus of the neonatal hippocampus. These alterations might disrupt fetal neurodevelopment during a vulnerable period.

New Insights from 22-kHz Ultrasonic Vocalizations to Characterize Fear Responses: Relationship with Respiration and Brain Oscillatory Dynamics.

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 θ and γ 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 prefrontal-amygdala 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 (USVs) 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 (LFPs) in BLA, mPFC, and olfactory piriform cortex (PIR), 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.

Increasing Role of Maternal Immune Activation in Neurodevelopmental Disorders.

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.

Understanding pup affective state through ethologically significant ultrasonic vocalization frequency.

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.

Ecologically relevant neurobehavioral assessment of the development of threat learning.

As altricial infants gradually transition to adults, their proximate environment changes. In three short weeks, pups transition from a small world with the caregiver and siblings to a complex milieu rich in dangers as their environment expands. Such contrasting environments require different learning abilities and lead to distinct responses throughout development. Here, we will review some of the learned fear conditioned responses to threats in rats during their ontogeny, including behavioral and physiological measures that permit the assessment of learning and its supporting neurobiology from infancy through adulthood. In adulthood, odor-shock conditioning produces robust fear learning to the odor that depends upon the amygdala and related circuitry. Paradoxically, this conditioning in young pups fails to support fear learning and supports approach learning to the odor previously paired with shock. This approach learning is mediated by the infant attachment network that does not include the amygdala. During the age range when pups transition from the infant to the adult circuit (10-15 d old), pups have access to both networks: odor-shock conditioning in maternal presence uses the attachment circuit but the adult amygdala-dependent circuit when alone. However, throughout development (as young as 5 d old) the attachment associated learning can be overridden and amygdala-dependent fear learning supported, if the mother expresses fear in the presence of the pup. This social modulation of the fear permits the expression of defense reactions in life threatening situations informed by the caregiver but prevents the learning of the caregiver itself as a threat.

Infant rats can learn time intervals before the maturation of the striatum: evidence from odor fear conditioning.

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.