Early handling and repeated cross-fostering have opposite effect on mouse emotionality

Early life events have a crucial role in programming the individual phenotype and exposure to traumatic experiences during infancy can increase later risk for a variety of neuropsychiatric conditions, including mood and anxiety disorders. Animal models of postnatal stress have been developed in rodents to explore molecular mechanisms responsible for the observed short and long lasting neurobiological effects of such manipulations. The main aim of this study was to compare the behavioral and hormonal phenotype of young and adult animals exposed to different postnatal treatments. Outbred mice were exposed to (i) the classical Handling protocol (H: 15 min-day of separation from the mother from day 1 to 14 of life) or to (ii) a Repeated Cross-Fostering protocol (RCF: adoption of litters from day 1 to 4 of life by different dams). Handled mice received more maternal care in infancy and showed the already described reduced emotionality at adulthood. Repeated cross fostered animals did not differ for maternal care received, but showed enhanced sensitivity to separation from the mother in infancy and altered respiratory response to 6% CO2 in breathing air in comparison with controls. Abnormal respiratory responses to hypercapnia are commonly found among humans with panic disorders (PD), and point to RCF-induced instability of the early environment as a valid developmental model for PD. The comparisons between short-and long-term effects of postnatal handling vs. RCF indicate that different types of early adversities are associated with different behavioral profiles, and evoke psychopathologies that can be distinguished according to the neurobiological systems disrupted by early-life manipulation

Early Social Enrichment Improves Social Motivation and Skills in a Monogenic Mouse Model of Autism, the Oprm1 −/− Mouse

Environmental enrichment has been proven to have positive effects on both behavioral and physiological phenotypes in rodent models of mental and neurodevelopmental disorders. In this study, we used mice lacking the -opioid receptor gene (Oprm1 −/− ), which has been shown to have deficits in social competence and communication, to assess the hypothesis that early enrichment can ameliorate sociability during development and adulthood. Due to the immaturity of sensory-motor capabilities of young pups, we chose as environmental stimulation a second lactating female, who provided extra maternal care and stimulation from birth. The results show that double mothering normalized the abnormal response to maternal separation in Oprm1 −/− pups and increased social motivation in juveniles and adult knockout mice. Additionally, we observed that Oprm1 −/− mice act as less attractive social partners than wild types, which suggests that social motivation can be modulated by the stimulus employed. This experiment supports previous findings suggesting that early social environmental stimulation has profound and long-term beneficial effects, encouraging the use of nonpharmacological interventions for the treatment of social defects in neurodevelopmental diseases

Analysis of visual cortical function and circuits in a mouse model of Rett- Syndrome

Rett Syndrome (RTT), a neurodevelopmental disorder, is caused by de novo mutation of MECP2 gene on X- chromosome and it is characterized by regression during the first few years of life. Specifically in the mouse visual cortex, evidence has shown that lack of Mecp2 disrupts development of inhibitory interneuron systems, leading to compromised balance of inhibitory and excitatory cortical neuronal function. In my thesis, I worked on Mecp2-heterozygous females, which are considered a closer model of the human condition. I performed visual evoked potential (VEP) in adult Mecp2 Het that exhibited either mild or severe RTT-like symptoms, according to the 12-point RTT phenotypic score (Guy et al., 2001). Mecp2 Het mice displayed a significant decrease in the amplitude of VEP response in comparison with their wild-type (WT) littermates. Interestingly, such defect was already present in Mecp2 Het mice with mild symptomatology and worsened with the disorder progression. Moreover, VEP response to high spatial frequencies was lost, resulting in a shift down in the spatial frequency (SF) tuning curve and significantly lower spatial resolution. I then tested whether administration of low dosage of NMDAR antagonist, ketamine (8mg/kg, ip) for six weeks (two weeks on/two weeks off) was sufficient to ameliorate the visual function in Mecp2 Het mice. I found an increase in the VEP amplitude in comparison with the Het treated with vehicle. In addition, we observed this increase in the response to all stimuli resulting in an amelioration of the visual acuity. Finally I characterized the inhibitory/excitatory imbalance in visual cortex using immunohistochemistry., finding an increase in the thalamic excitatory markers that precedes the full onset of the regression. Together our results indicate that visual processing is impaired across Mecp2 mouse models and provide further evidence that targeting NMDAR function is a feasible and an effective therapeutic treatment for Rett Syndrome

Early Social Enrichment Improves Social Motivation and Skills in a Monogenic Mouse Model of Autism, the Oprm1−/− Mouse

Environmental enrichment has been proven to have positive effects on both behavioral and physiological phenotypes in rodent models of mental and neurodevelopmental disorders. In this study, we used mice lacking the µ-opioid receptor gene (Oprm1−/−), which has been shown to have deficits in social competence and communication, to assess the hypothesis that early enrichment can ameliorate sociability during development and adulthood. Due to the immaturity of sensory-motor capabilities of young pups, we chose as environmental stimulation a second lactating female, who provided extra maternal care and stimulation from birth. The results show that double mothering normalized the abnormal response to maternal separation in Oprm1−/− pups and increased social motivation in juveniles and adult knockout mice. Additionally, we observed that Oprm1−/− mice act as less attractive social partners than wild types, which suggests that social motivation can be modulated by the stimulus employed. This experiment supports previous findings suggesting that early social environmental stimulation has profound and long-term beneficial effects, encouraging the use of nonpharmacological interventions for the treatment of social defects in neurodevelopmental diseases

The neural substrate of spatial memory stabilization depends on the distribution of the training sessions

Distributed training is known to lead to more robust memory formation as compared to training experiences with short intervals. Although this phenomenon, termed distributed practice effect, ubiquitous over a wide variety of tasks and organisms, has long been known by psychologists, its neurobiological underpinning is still poorly understood. Using the striatum as a model system here we tested the hypothesis that the ability of distributed training to optimize memory might depend upon the recruitment of different neural substrates compared to those engaged by massed training. First, by contrasting the medial and the lateral domains of the dorsal striatum after massed and distributed training we demonstrated that neuronal activity, as assessed using c-Fos expression, is differentially affected by the training protocol in the two striatal subregions. Next, by blocking the AMPA receptors before recall we provide evidence to support a selective role of the medial and the lateral striatum in the storage of information acquired respectively by massed and distributed training. Finally, we found that optogenetic stimulation of the dorsolateral striatum during massed training enables the formation of an enduring memory similarly to what is observed with distributed learning. Overall, these findings identify a possible mechanism for the distributed practice effect, a still poorly understood aspect of learning

Specific patterns of neural activity in the hippocampus after massed or distributed spatial training

Abstract Training with long inter-session intervals, termed distributed training, has long been known to be superior to training with short intervals, termed massed training. In the present study we compared c-Fos expression after massed and distributed training protocols in the Morris water maze to outline possible differences in the learning-induced pattern of neural activation in the dorsal CA1 in the two training conditions. The results demonstrate that training and time lags between learning opportunities had an impact on the pattern of neuronal activity in the dorsal CA1. Mice trained with the distributed protocol showed sustained neuronal activity in the postero-distal component of the dorsal CA1. In parallel, in trained mice we found more active cells that tended to constitute spatially restricted clusters, whose degree increased with the increase in the time lags between learning trials. Moreover, activated cell assemblies demonstrated increased stability in their spatial organization after distributed as compared to massed training or control condition. Finally, using a machine learning algorithm we found that differences in the number of c-Fos positive cells and their location in the dorsal CA1 could be predictive of the training protocol used. These results suggest that the topographic organization and the spatial location of learning activated cell assemblies might be critical to promote the increased stability of the memory trace induced by distributed training

Visual evoked potentials detect cortical processing deficits in Rett syndrome

ObjectiveRett syndrome (RTT) is a neurodevelopmental disorder caused by mutation of the X-linked MECP2 gene and characterized by developmental regression during the first few years of life. The objective of this study was to investigate if the visual evoked potential (VEP) could be used as an unbiased, quantitative biomarker to monitor brain function in RTT. MethodsWe recorded pattern-reversal VEPs in Mecp2 heterozygous female mice and 34 girls with RTT. The amplitudes and latencies of VEP waveform components were quantified, and were related to disease stage, clinical severity, and MECP2 mutation type in patients. Visual acuity was also assessed in both mice and patients by modulating the spatial frequency of the stimuli. ResultsMecp2 heterozygous female mice and RTT patients exhibited a similar decrease in VEP amplitude that was most striking in the later stages of the disorder. RTT patients also displayed a slower recovery from the principal peak of the VEP response that was impacted by MECP2 mutation type. When the spatial frequency of the stimulus was increased, both patients and mice displayed a deficit in discriminating smaller patterns, indicating lower visual spatial acuity in RTT. InterpretationVEP is a method that can be used to assess brain function across species and in children with severe disabilities like RTT. Our findings support the introduction of standardized VEP analysis in clinical and research settings to probe the neurobiological mechanism underlying functional impairment and to longitudinally monitor progression of the disorder and response to treatmen

Impact of diffused versus vasculature targeted DNA damage on the heart of mice depleted of telomeric factor Ft1

: DNA damage is emerging as a driver of heart disease, although the cascade of events, its timing, and the cell types involved are yet to be fully clarified. In this context, the implication of cardiomyocytes has been highlighted, while that of vasculature smooth muscle cells has been implicated but not explored exhaustively. In our previous work we characterized a factor called Ft1 in mice and AKTIP in humans whose depletion generates telomere instability and DNA damage. Herein, we explored the effect of the reduction of Ft1 on the heart with the goal of comparatively defining the impact of DNA damage targeted to vasculature smooth muscle cells to that of diffuse damage. Using two newly generated mouse models, Ft1 constitutively knocked out (Ft1ko) mice, and mice in which we targeted the Ft1 depletion to the smooth muscle cells (Ft1sm22ko), it is shown that both genetic models display cardiac defects but with differences. Both Ft1ko and Ft1sm22ko mice display hypertrophy, fibrosis, and functional heart defects. Interestingly, Ft1sm22ko mice have early milder pathological traits that become manifest with age. Significantly, the defects of Ft1ko mice, including the alteration of the left ventricle and functional heart defects, are rescued by depletion of the DNA damage sensor p53. These results point to Ft1 deficiency as a driver of cardiac disease and show that Ft1 deficiency targeted to vasculature smooth muscle cells generates a pre-pathological profile exacerbated by age