Tactile stimulation facilitates functional recovery and dendritic change following neonatal hemidecortication in rats.

After large neocortical lesions, such as hemidecortication, children can show significant motor and cognitive impairments. It thus is of considerable interest to identify treatments that might enhance long-term functional outcome. We have previously shown that tactile stimulation enhances recovery from perinatal focal cortical lesions in rats, so the goal of the present experiment was to explore the effectiveness of postlesion tactile stimulation in reducing functional deficits associated with neonatal hemidecortication. Rats were given hemidecortications on postnatal day 10 (P10). Half of the group was then exposed to a daily tactile stimulation treatment for 15 min, three times a day for eleven days following the surgery. All groups were then tested on a number of behavioural tasks (Morris water task, skilled reaching, forelimb placing during spontaneous vertical exploration, and a sunflower seed opening task) beginning at P 120. The brains of the male animals were prepared for Golgi-Cox staining and subsequent analysis of dendritic arborisation and spine density. There were two main findings in this experiment: 1) Tactile stimulation improved cognitive ability and some motor performance after P 10 hemidecortication; and, 2) Tactile stimulation altered cortical organization after P10 hemidecortication. Tactile stimulation may provide an important noninvasive therapy after hemispherectomy in children.

Comparison of motor recovery after neonatal and adult hemidecortication.

Hemidecortication produces a wide range of cognitive and motor symptoms in both children and lab animals that are generally far greater than smaller bilateral focal lesions of cerebral cortex. Although there have been many studies of motor functions after hemidecortication, the analyses largely have been of general motor functions rather than of more skilled motor functions such as forelimb reaching. The objective of the present experiment was to analyze the sensorimotor forelimb function of rats after infant or adult hemidecortication by utilizing multiple motor analyses. Rats were given hemidecortications either on postnatal day 10 (P10) or day 90 (P90). Both groups were then tested on a number of behavioural tasks (two tests of skilled reaching, forelimb placing during spontaneous vertical exploration, and a sunflower seed opening task) beginning at P 120. In a portion of the P10 female animals, topographic movement representations were derived in the hemisphere contralateral to lesion using Intracortical Microstimulation (ICMS). The brains of the male animals were prepared for Golgi-Cox staining and subsequent analysis of dendritic arborisation and spine density. There were three main findings. 1) Both groups of hemidecorticate animals were impaired when tested on the motor tasks, but the impairments were qualitatively different in the neonatal and adult operates. For example, the P 10 hemidecorticate animals displayed simultaneous bilateral forelimb movement, or "mirror movements." 2) Hemidecortication at P90 but not P10, led to increased dendritic arborisation of Layer III pyramidal cells in the intact parietal cortex but whereas P90 animals showed a decrease in cortical thickness in the intact hemisphere, the P10 animals do not, even though there are no callosal connections. 3) P10 hemidecortication altered the details of the ICMS-delineated motor maps in a small group of female hemidecorticates that were studied. In conclusion, there was postinjury compensation for motor impairments in both P10 and P90 rats but the mechanisms were different. Furthermore, comparisons of postinjury behavioral and anatomical compensation in rats with focal cortical injuries at those ages in our previous studies showed marked differences. These results suggest that there is a fundamental difference in the way that the brain compensates from hemidecortication and focal injury in development.

Acute gut inflammation reduces neural activity and spine maturity in hippocampus but not basolateral amygdala.

Gastrointestinal tract (gut) inflammation increases stress and threat-coping behaviors, which are associated with altered activity in fear-related neural circuits, such as the basolateral amygdala and hippocampus. It remains to be determined whether inflammation from the gut affects neural activity by altering dendritic spines. We hypothesized that acute inflammation alters dendritic spines in a brain region-specific manner. Here we show that acute gut inflammation (colitis) evoked by dextran sodium sulfate (DSS) did not affect the overall spine density in the CA1 region of hippocampus, but increased the relative proportion of immature spines to mature spines on basal dendrites of pyramidal neurons. In contrast, in animals with colitis, no changes in spine density or composition on dendrites of pyramidal cells was observed in the basolateral amygdala. Rather, we observed decreased spine density on dendrites of stellate neurons, but not the relative proportions of mature vs immature spines. We used cFos expression evoked by the forced swim task as a measure of neural activity during stress and found no effect of DSS on the density of cFos immunoreactive neurons in basolateral amygdala. In contrast, fewer CA1 neurons expressed cFos in mice with colitis, relative to controls. Furthermore, CA1 cFos expression negatively correlated with active stress-coping in the swim task and was negatively correlated with gut inflammation. These data reveal that the effects of acute gut inflammation on synaptic remodeling depend on brain region, neuronal phenotype, and dendrite location. In the hippocampus, a shift to immature spines and hypoactivity are more strongly related to colitis-evoked behavioral changes than is remodeling in basolateral amygdala.

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.

Which hand knows the "right" word? What hand selection reveals about vocabulary in pre-and school-aged children.

Research has shown that infants with increased right-hand selection for their first gestures perform better at an array of language tasks when they are tested later as toddlers. There is a smaller body of literature which focuses on preschoolers and how their right-handed movements relate to their speech and vocabulary development. Some research has established a connection between right-hand preference for grasping and speech production ability in preschool children, but the link to gestures is relatively unexplored in this age group. We investigated if lateralized gestures (pointing) are related to measures of language development (vocabulary) in a preschool-age sample. Specifically, typically developing children (aged 3-6) completed the Peabody Picture Vocabulary Test (PPVT) to assess receptive language. We recorded their hand preference for pointing during the PPVT and the incidence of mistakes (pointing to the wrong picture). Despite the length of the test, children were more likely to select a correct response with their right hand. This result suggests a relationship between lateralized communicative gestures (pointing) and receptive language. This study provides evidence for an intimate relationship between right-handed manual movement and language development. Implications of this finding include developing simple fine-motor tasks to detect and/or ameliorate delayed language development.

Promoting Executive Function Skills in Preschoolers Using a Play-Based Program.

In recent years, play has been shown to be a powerful means to enhance learning and brain development. It is also known that through play children enhance their executive function (EF) skills. Furthermore, well-developed EF in preschoolers has been shown to be an important predictor for later academic and life success. Armed with this information a program, Building Brains and Futures (BBF), for developing EF through play was designed for 3-5-year-old. The program consisted of 10 simple, fun, and interactive games selected to enhance various facets of EF. The 10 games included were: dimensional change card sort, lips and ears, block building, musical freeze, opposites, pretend play, red light/green light, shared project, Simon says, and wait for it. The program was implemented with a group of children shown to have challenges with respect to kindergarten readiness. The approach was first, to build adult capability by sharing knowledge of brain development, EF, and the importance of play with educators, caregivers, and parents. Second, to build skills in delivering the program in the school setting. Children engaged with the program of games for a minimum of 6 weeks. Their performance on a battery of direct measures of EF, language, and motor skills, were recorded before and after the program. The results showed improvement in all three domains. In addition, adopters of the BBF program reported it was easily and successfully integrated into their existing preschool curricula. The importance of intentional adult directed play in building developmental learning, including EF, is discussed.

The association between sedentary behavior and cognitive ability in older adults.

Executive functions (EF) are a grouping of cognitive abilities essential for daily life. Previous research has shown that physical activity (PA) may in fact preserve EF in older adults, but the link between sedentary behavior (SB) and cognitive ability has been less explored. The purpose of this study was to examine the relationship between SB and cognition (executive function and memory) in older adults. Seventy five older adults (74.6 ± 9 years) self-reported their sedentary time (ST) and PA, as well as EF ability (paper-based measure of EF). Participants also completed several performance-based measures of EF and a memory task. Older adults who were less sedentary had superior EF and memory (e.g., Stroop time was significantly faster in less sedentary adults (34.7 s ± 1.9) compared to more sedentary adults (39.6 s ± 1.8), p = .02). Regression analysis showed that total ST was associated with several measures of EF after adjusting for age, and physical activity (e.g., Stroop time ß = .005 (.002, .009). Less cognitively demanding SB (TV viewing and napping) was associated with worse performance on most EF and in the memory task. Performing a hobby was also associated with lower levels of EF and memory. For example, the building times for the Lego task were positively related to napping (r2 = .34), watching TV (r2 = .27), and performing a hobby (r2 = .46). Associations of ST with cognitive abilities were more pronounced in older adults who engaged in less PA. These results suggest that SB may play an important role in cognitive abilities of older adults. Longitudinal studies using performance-based assessments of EF are needed. Lara Coelho and Kayla Hauck contributed equally to the manuscript.

Neonatal tactile stimulation reverses alterations in fine structure of small, but not large myelinated fibers, from the optic nerve of iron-deficient rats: A size-based selectivity.

Iron is the most common micronutrient deficiency in the world and it is most prevalent in young children, exposing their developing brain to inadequate iron levels. The damage related to neuroanatomical parameters is not reversed after iron treatment. However, evidence suggest that tactile stimulation (TS) may offer great therapeutic efficacy in cases of nutritional disorders postnatally, since the brain is remarkably responsive to its interaction with the environment. Recently, we shown that neonatal iron deficient rats achieved some remedial effect by exposing them to TS treatment early in life, reinforcing the fact that the TS approach is a positive enriching experience, therefore, here we ask whether exposure to TS treatment, could also be employed to prevent fine structural changes in the fibers from optic nerve of rats maintained on an iron-deficient diet during brain development. To elucidate the protective effect of tactile stimulation, our methods resulted in 10,859 analyzed fibers, divided into small and large fibers. We found that iron deficiency led to a decreased axon, fiber and myelin size of small fibers, however, TS completely reversed the iron-decifiency-induced alteration on those fiber measurements. Large fibers were disproportionately affected by iron deficiency and there was no remediating effect due to tactile stimulation treatment. The present study adds new information regarding different alterations between small and large fibers due to diet and TS, which suggest a size-based selectivity. These results emphasize the concept that compromised brain development can be mitigated at an early age by environmental factors, such as tactile stimulation.

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.

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.

Sensorimotor lateralization scaffolds cognitive specialization.

In this chapter, we review hemispheric differences for sensorimotor function and cognitive abilities. Specifically, we examine the left-hemisphere specialization for visuomotor control and its interplay with language, executive function, and musical training. Similarly, we discuss right-hemisphere lateralization for haptic processing and its relationship to spatial and numerical processing. We propose that cerebral lateralization for sensorimotor functions served as a foundation for the development of higher cognitive abilities and their hemispheric functional specialization. We further suggest that sensorimotor and cognitive functions are inextricably linked. Based on the studies discussed in this chapter our view is that sensorimotor control serves as a loom upon which the fibers of language, executive function, spatial, and numerical processing are woven together to create the fabric of cognition.

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.

Articulation Speaks to Executive Function: An Investigation in 4- to 6-Year-Olds.

Executive function (EF) and language learning play a prominent role in early childhood development. Empirical research continues to point to a concurrent relation between these two faculties. What has been given little attention, however, is the association between EF and speech articulation abilities in children. This study investigated this relation in children aged 4-6 years. Significant correlations indicated that children with better EF [via parental report of the Behavior Rating Inventory of Executive Function (BRIEF) inventory] exhibited stronger speech sound production abilities in the articulation of the "s" and "sh" sounds. Furthermore, regression analyses revealed that the Global Executive Composite (GEC) of EF as measured by the BRIEF, served as a predictor for speech sound proficiency and that speech sound proficiency served as a predictor for the GEC. Together, these results demonstrate the imbricated nature of EF and speech sound production while bearing theoretical and practical implications. From a theoretical standpoint, the close link between EF and speech articulation may indicate a common ontogenetic pathway. From a practical perspective, the results suggest that children with speech difficulties could be at higher risk for EF deficits.

Sex differences in rat decision-making: The confounding role of extraneous feeder sampling between trials.

Although male and female rats appear to perform differently in some tasks, a clear picture of sex differences in decision-making has yet to develop. This is in part due to significant variability arising from differences in strains and tasks. The aim of this study was to characterize the effects of sex on specific response elements in a reinforcement learning task so as to help identify potential explanations for this variability. We found that the primary difference between sexes was the propensity to approach feeders out of the task context. This extraneous feeder sampling affects choice on subsequent trials in both sexes by promoting a lose-shift response away from the last feeder sampled. Female rats, however, were more likely to engage in this extraneous feeder sampling, and therefore exhibited a greater rate of this effect. Once trials following extraneous sampling were removed, there were no significant sex differences in any of the tested measures. These data suggest that feeder approach outside of the task context, which is often not recorded, could produce a confound in sex-based differences of reinforcement sensitivity in some tasks.

Visual Field Advantage: Redefined by Training?

Previc (1990) postulated that most peri-personal space interactions occurred in the lower visual field (LVF), leading to an advantage when compared to the upper visual field (UVF). It is not clear if extensive practice can affect the difference between interactions in the LVF/UVF. We tested male and female basketball varsity athletes and non-athletes on a DynaVision D2 visuomotor reaction task. We recruited basketball players because in their training they spend significant amount of time processing UVF information. We found a LVF advantage in all participants, but this advantage was significantly reduced in the athletes. The results suggest that training can be a powerful modulator of visuomotor function.

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.

Tactile stimulation partially prevents neurodevelopmental changes in visual tract caused by early iron deficiency.

Iron deficiency has a critical impact on maturational mechanisms of the brain and the damage related to neuroanatomical parameters is not satisfactorily reversed after iron replacement. However, emerging evidence suggest that enriched early experience may offer great therapeutic efficacy in cases of nutritional disorders postnatally, since the brain is remarkably responsive to its interaction with the environment. Given the fact that tactile stimulation (TS) treatment has been previously shown to be an effective therapeutic approach and with potential application to humans, here we ask whether exposure to TS treatment, from postnatal day (P) 1 to P32 for 3min/day, could also be employed to prevent neuroanatomical changes in the optic nerve of rats maintained on an iron-deficient diet during brain development. We found that iron deficiency changed astrocyte, oligodendrocyte, damaged fiber, and myelinated fiber density, however, TS reversed the iron-deficiency-induced alteration in oligodendrocyte, damaged fiber and myelinated fiber density, but failed to reverse astrocyte density. Our results suggest that early iron deficiency may act by disrupting the timing of key steps in visual system development thereby modifying the normal progression of optic nerve maturation. However, optic nerve development is sensitive to enriching experiences, and in the current study we show that this sensitivity can be used to prevent damage from postnatal iron deficiency during the critical period.

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.