Development of ultrasonic calls in rat pups follows similar patterns regardless of isolation distress.

Ultrasonic vocalizations (USVs) emitted by rat pups have been extensively studied in the context of isolation from their mother and littermates. The heightened call rate of isolation-induced USVs indicates increased anxiety, whereas other acoustic parameters, such as frequency and call duration, are thought to be useful in reflecting developmental changes, which by weaning have developed into their adult form. However, it is possible that stress can affect the quality as well as the quantity of calls, and that as the pups become more mobile, the effects of the stress may change. Therefore, in the present study rats were tested in a test arena either in isolation or with littermates, so as to assess the effects of isolation stress on the developmental changes reported in the literature. Rat pups of both sexes were tested on multiple days from postnatal day (PND) 7 to weaning. Overall, the main changes in the frequency, duration, and types of calls were accounted for by age. The effects of isolation were minor, as were sex differences. This study indicates that the development of USVs in infant rats is a robust process and seemingly resistant to the effects of isolation-induced stress.

Principles of plasticity in the developing brain.

The developing brain is especially sensitive to a wide range of experiences, showing a remarkable capacity for plastic changes that influence behavioural outcomes throughout the lifetime. We review the principles that regulate this plasticity in development and consider the factors that modulate the developing brain. These include early sensory, motor, and language experience, early stress, caregiver interactions, peer interactions, psychoactive drugs, diet, microbiome, and the immune system. Emphasis is given to changes in behaviour, epigenetics, and neuronal morphology. WHAT THIS PAPER ADDS: A discussion of the surprising range of factors influencing brain development Life experiences interact resulting in a phenomenon called metaplasticity.

Effects of prenatal exposure to valproic acid on the development of juvenile-typical social play in rats.

Autism is a severe neurodevelopmental disorder characterized by qualitative impairments in social behavior, communication, and aberrant repetitive behaviors. A major focus of animal models of autism has been to mimic the social deficits of the disorder. The present study assessed whether rats exposed prenatally to valproic acid (VPA) show deficits in social play as juveniles that are consistent with the social deficits observed in autism. Dams were exposed to an acute dose of VPA on gestational day 12.5. Later, the playful interactions and associated ultrasonic vocalizations of the juveniles were examined. It was predicted that VPA-treated rats should play less than the controls. Characteristic of neurobehavioral insult at this early age, the VPA-treated juveniles showed significant increases in the frequency of body shakes and sexual mounting, but played at the same frequency as the controls. However, when playing, they were less likely to use tactics that facilitated bodily contact and vocalized less. These data suggest that prenatal VPA exposure disrupts some aspects of being able to communicate effectively and engage partners in dynamic interactions - deficits that are consistent with those observed in autism.

Distinct sex-dependent effects of maternal preconception nicotine and enrichment on the early development of rat offspring brain and behavior.

Developmental nicotine exposure is harmful to offspring. Whereas much is known about the consequences of prenatal nicotine exposure, relatively little is understood about how maternal preconception nicotine impacts the next generation. Positive experiences, such as environmental enrichment/complexity, have considerable potential to improve developmental outcomes and even treat and prevent drug addiction. Therefore, the current study sought to identify how maternal exposure to moderate levels of nicotine prior to conception impacts offspring development, and if the presumably negative consequence of nicotine could be reversed by concurrent exposure to an enriched environment. We treated female Long Evans rats with nicotine in their drinking water (15 mg nicotine salt/L) for seven weeks while residing in either standard or enriched conditions. Both experiences occurred exclusively prior to mating. Nicotine exposure reduced dam fertility by ~20% (p = .06). Females reared their own litters, and offspring were tested in two assessments of early development: negative geotaxis and open field. Offspring were euthanized at weaning (P21), and their brains were processed with Golgi-Cox solution to allow quantification of dendritic spine density. Results indicate that neither maternal nicotine or enrichment had an impact on maternal care, but male offspring were impaired at negative geotaxis due to maternal nicotine, female offspring showed altered open field exploration due to maternal enrichment, and offspring of both sexes had increased spine density in OFC due to maternal enrichment. Therefore, this experiment provides novel insights into the unique, sex-dependent consequences of maternal preconception nicotine and enrichment on the early development of rat behavior and brain.

Maternal stress prior to conception impairs memory and decreases right dorsal hippocampal volume and basilar spine density in the prefrontal cortex of adult male offspring.

Chronic parental stress impacts offspring functioning throughout life. Chronic variable stress prior to conception impairs offspring development in terms of behavior, neuroanatomy, and neurobiology. Previously, our lab demonstrated that even a consistent stressor experienced by the sire or the dam shapes offspring development beginning in early life. Here, we show how consistent maternal stress prior to conception influences the brain and behavior of offspring in adolescence and adulthood. Female Long-Evans rats were exposed to elevated platform stress twice daily for 27 consecutive days immediately prior to mating with non-stressed males. Male and female offspring were assessed in the open field and elevated plus maze in adolescence, and open field, elevated plus maze, Whishaw tray reaching, and Morris water task in adulthood. Offspring were then euthanized, and their brains were stained with Golgi-Cox solution and then examined for dendritic spine density and hippocampal volume. Major findings include deficits in spatial memory, decreased medial prefrontal cortex spine density, and reduced right dorsal hippocampal volume in male offspring only. This work illustrates that the effects of consistent maternal stress prior to conception are lifelong and highly sexually dimorphic.

A Neural Network Reveals Motoric Effects of Maternal Preconception Exposure to Nicotine on Rat Pup Behavior: A New Approach for Movement Disorders Diagnosis.

Neurodevelopmental disorders can stem from pharmacological, genetic, or environmental causes and early diagnosis is often a key to successful treatment. To improve early detection of neurological motor impairments, we developed a deep neural network for data-driven analyses. The network was applied to study the effect of maternal nicotine exposure prior to conception on 10-day-old rat pup motor behavior in an open field task. Female Long-Evans rats were administered nicotine (15 mg/L) in sweetened drinking water (1% sucralose) for seven consecutive weeks immediately prior to mating. The neural network outperformed human expert designed animal locomotion measures in distinguishing rat pups born to nicotine exposed dams vs. control dams (87 vs. 64% classification accuracy). Notably, the network discovered novel movement alterations in posture, movement initiation and a stereotypy in "warm-up" behavior (repeated movements along specific body dimensions) that were predictive of nicotine exposure. The results suggest novel findings that maternal preconception nicotine exposure delays and alters offspring motor development. Similar behavioral symptoms are associated with drug-related causes of disorders such as autism spectrum disorder and attention-deficit/hyperactivity disorder in human children. Thus, the identification of motor impairments in at-risk offspring here shows how neuronal networks can guide the development of more accurate behavioral tests to earlier diagnose symptoms of neurodevelopmental disorders in infants and children.

Maternal Preconception Stress Alters Prefrontal Cortex Development in Long-Evans Rat Pups without Changing Maternal Care.

Stress during development can shift the typical developmental trajectory. Maternal stress prior to conception has recently been shown to exert similar influences on the offspring. The present study questioned if a consistent maternal stressor prior to conception (elevated platform stress) would impact the pre-weaning development of offspring brain and behavior, and if maternal care was vulnerable to this experience. Adult female Long-Evans rats were subjected to elevated platform stress for 27 days prior to mating with non-stressed males. Maternal care was monitored, and pups were assessed in two tests of early behavioral development, negative geotaxis and open field. Pups were perfused at weaning and their brains were extracted and stained with Cresyl Violet, allowing gross measurements of cortical and subcortical structures and estimates of neuron density. Main findings indicate that a change in prefrontal cortical thickness is evident despite no change in maternal care. Female offspring show a decrease in medial-dorsal thalamus size. The current study failed to find an effect of maternal preconception stress on early behavioral development. These results suggest that the PFC, and likely behavior dependent on the PFC, is vulnerable to maternal preconception stress and that a strong sex effect is evident. Further studies should examine how such offspring fare using a lifespan model and investigate potential mechanisms responsible for these effects.

Preconception Paternal Stress in Rats Alters Brain and Behavior in Offspring.

Whereas environmental challenges during gestation have been repeatedly shown to alter offspring brain architecture and behavior, exploration examining the consequences of paternal preconception experience on offspring outcome is limited. The goal of this study was to examine the effects of preconception paternal stress (PPS) on cerebral plasticity and behavior in the offspring. Several behavioral assays were performed on offspring between postnatal days 33 (P33) and 101 (P101). Following behavioral testing, the brains were harvested and dendritic morphology (dendritic complexity, length, and spine density) were examined on cortical pyramidal cells in medial prefrontal cortex (mPFC), orbital frontal cortex (OFC), parietal cortex (Par1), and the CA1 area of the hippocampus. As anticipated, behavior was altered on both the activity box assay and elevated plus maze and performance was impaired in the Whishaw tray reaching task. Neuroanatomical measures revealed a heavier brain in stressed animals and dendritic changes in all regions measured, the precise effect varying with the measure and cerebral region. Thus, PPS impacted both behavior and neuronal morphology of offspring. These effects likely have an epigenetic basis given that in a parallel study of littermates of the current animals we found extensive epigenetic changes at P21.

The role of the medial prefrontal cortex in regulating interanimal coordination of movements.

Rats with juvenile play experience display a greater ability in coordinating their movements with social partners than those deprived of such experience, and this may be due to the play-induced neural restructuring of the medial prefrontal cortex (mPFC). The present study investigates the role of the mPFC in interanimal coordination. Rats with and without bilateral mPFC lesions were tested on a robbing-and-dodging task. This food protection task measures the ability of rats to protect pieces of food by gaining and maintaining an interanimal distance between themselves and the rat attempting to rob the food. Given that mPFC lesions have been associated with sensory and motor deficits, the same rats were also subjected to a task to measure skilled motor movements. Rats with bilateral mPFC lesions had more food stolen and displayed an inability to maintain interanimal distance with partner, but did not exhibit any motor or sensory deficits. These findings suggest that the mPFC is involved in interanimal coordination and that the play-induced neural restructuring of this area may account for the enhanced coordination seen in rats with prior play experience.