Allonna Harker

Paternal stress prior to conception alters DNA methylation and behaviour of developing rat offspring.

Although there has been an abundance of research focused on offspring outcomes associated with maternal experiences, there has been limited examination of the relationship between paternal experiences and offspring brain development. As spermatogenesis is a continuous process, experiences that have the ability to alter epigenetic regulation in fathers may actually change developmental trajectories of offspring. The purpose of this study was to examine the effects of paternal stress prior to conception on behaviour and the epigenome of both male and female developing rat offspring. Male Long-Evans rats were stressed for 27 consecutive days and then mated with control female rats. Early behaviour was tested in offspring using the negative geotaxis task and the open field. At P21 offspring were sacrificed and global DNA methylation levels in the hippocampus and frontal cortex were analysed. Paternal stress prior to conception altered behaviour of all offspring on the negative geotaxis task, delaying acquisition of the task. In addition, male offspring demonstrated a reduction in stress reactivity in the open field paradigm spending more time than expected in the centre of the open field. Paternal stress also altered DNA methylation patterns in offspring at P21, global methylation was reduced in the frontal cortex of female offspring, but increased in the hippocampus of both male and female offspring. The results from this study clearly demonstrate that paternal stress during spermatogenesis can influence offspring behaviour and DNA methylation patterns, and these affects occur in a sex-dependent manner. Development takes place in the centre of a complex interaction between maternal, paternal, and environmental influences, which combine to produce the various phenotypes and individual differences that we perceive.

Preconception paternal stress in rats alters dendritic morphology and connectivity in the brain of developing male and female offspring

The goal of this research was to examine the effect of preconception paternal stress (PPS) on the subsequent neurodevelopment and behavior of male and female offspring. Prenatal (gestational) stress has been shown to alter brain morphology in the developing brain, and is presumed to be a factor in the development of some adult psychopathologies. Our hypothesis was that paternal stress in the preconception period could impact brain development in the offspring, leading to behavioral abnormalities later in life. The purpose of this study was to examine the effect of preconception paternal stress on developing male and female offspring brain morphology in five brain areas; medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), parietal cortex (Par1), hippocampus (CA1) and nucleus accumbens (NAc). Alterations in dendritic measures and spine density were observed in each brain area examined in paternal stress offspring. Our two main findings reveal; (1) PPS alters brain morphology and organization and these effects are different than the effects of stress observed at other ages; and, (2) the observed dendritic changes were sexually dimorphic. This study provides direct evidence that PPS modifies brain architecture in developing offspring, including dendritic length, cell complexity, and spine density. Alterations observed may contribute to the later development of psychopathologies and maladaptive behaviors in the offspring.

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.

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.

Tactile stimulation improves neuroanatomical pathology but not behavior in rats prenatally exposed to valproic acid.

Autism is a severe neurodevelopmental disorder with a population prevalence of 1 in 68, and dramatically increasing. While no single pharmacologic intervention has successfully targeted the core symptoms of autism, emerging evidence suggests that postnatal environmental manipulations may offer greater therapeutic efficacy. Massage therapy, or tactile stimulation (TS), early in life has repeatedly been shown to be an effective, low-cost, therapeutic approach in ameliorating the cognitive, social, and emotional symptoms of autism. While early TS treatment attenuates many of the behavioral aberrations among children with autism, the neuroanatomical correlates driving such changes are unknown. The present study assessed the therapeutic effects of early TS treatment on behavior and neuroanatomy using the valproic acid (VPA) rodent model of autism. Rats were prenatally exposed to VPA on gestational day 12.5 and received TS shortly following birth. Whereas TS reversed almost all the VPA-induced alterations in neuroanatomy, it failed to do so behaviorally. The TS VPA animals, when compared to VPA animals, did not exhibit altered or improved behavior in the delayed non-match-to-sample T-maze, Whishaw tray reaching, activity box, or elevated plus maze tasks. Anatomically, however, there were significant increases in dendritic branching and spine density in the medial prefrontal cortex, orbital frontal cortex, and amygdala in VPA animals following early TS treatment, suggesting a complete reversal or remediation of the VPA-induced effects in these regions. The results suggest that postnatal TS, during a critical period in development, acts as a powerful reorganization tool that can ameliorate the neuroanatomical consequences of prenatal VPA exposure.

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.

Social Dysfunction: The Effects of Early Trauma and Adversity on Socialization and Brain Development

Abstract Research over the past 60 years has shown that early stress predisposes individuals to a range of maladaptive behaviors and psychopathologies including drug addiction, depression, and schizophrenia. Although there is likely a genetic predisposition for individuals to respond poorly to early stressors, genome-wide association scans have failed to identify major gene(s) linked to psychiatric disease. Rather, as described in detail in Chapter 7, Epigenetics and Genetics of Brain Development, the emerging field of epigenetics has provided a mechanism to account for the effect of stress, including early aversive experiences, on brain and behavioral development. In this chapter, we will review the behavioral effects of various forms of stress in development, in addition to adverse early experiences during childhood and adolescence. We then consider the consequences of adverse experiences on developing brain structure and neurocognition. In addition, we consider the role of the family and socioeconomic status on brain and behavioral development. Finally, we examine the complex interplay between genetics, epigenetics, and experience in relation to resiliency.

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.

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.