Currently, little is known about the effect of environmental enrichment (EE) on astrocytic plasticity, especially during aging. Given the newly discovered role of the astrocytes in regulating the synaptic transmission and thereby, the cognitive functions, we aimed to study the impact of EE on the performance in a spatial memory task and on the number and morphology of GFAP immunopositive cells in the dorsal hippocampus. After two months of EE (3 h/per day), the animals were tested in the Radial-Arm Water Maze (RAWM) for four days, with six daily trials. Next, we analyzed the changes in the GFAP immunopositive cells in CA1, CA3 and Dentate Gyrus (DG). Behavioral results showed that, even in advanced ages, EE improved the performance in a spatial memory task. Also, we found that aged rats submitted to EE had more GFAP immunopositive cells in the DG and more complex astrocytes, revealed by Sholl analysis, in all hippocampal subfields with respect to the other experimental conditions. Interestingly, the learning of a spatial memory task produced more morphological complexity and higher levels of GFAP immunopositive cells with regard to a standard control group, but not at the same level of the enriched groups. Thus, it is possible that the plastic changes found in the hippocampal astrocytes after EE are involved in a brain reserve to cope with age-related cognitive impairments.

Environmental enrichment (EE) is an experimental setting broadly used for investigating the effects of complex social, cognitive, and sensorimotor stimulations on brain structure and function. Recent studies point out that parental EE experience, even occurring in the pre-reproductive phase, affects neural development and behavioral trajectories of the offspring. In the present study we investigated the influences of pre-reproductive EE of female rats on maternal behavior and adolescent male offspring's coping response to an inescapable stressful situation after chronic social isolation. For this purpose female Wistar rats were housed from weaning to breeding age in enriched or standard environments. Subsequently, all females were mated and housed in standard conditions until offspring weaning. On the first post partum day (ppd 1), mother-pup interactions in undisturbed conditions were recorded. Further, after weaning the male pups were reared for 2 weeks under social isolation or in standard conditions, and then submitted or not to a single-session Forced Swim Test (FST). Offspring's neuronal activation and plastic changes were identified by immunohistochemistry for c-Fos and glucocorticoid receptors (GRs), and assessed by using stereological analysis. The biochemical correlates were measured in the hippocampus, amygdala and cingulate cortex, structures involved in hypothalamic-pituitary-adrenocortical axis regulation. Enriched dams exhibited increased Crouching levels in comparison to standard reared dams. In the offspring of both kinds of dams, social isolation reduced body weight, decreased Immobility, and increased Swimming during FST. Moreover, isolated offspring of enriched dams exhibited higher levels of Climbing in comparison to controls. Interestingly, in the amygdala of both isolated and control offspring of enriched dams we found a lower number of c-Fos immunopositive cells in response to FST and a higher number of GRs in comparison to the offspring of standard dams. These results highlight the profound influence of a stressful condition, such as the social isolation, on the brain of adolescent rats, and underline intergenerational effects of maternal experiences in regulating the offspring response to stress.

As major components of neuronal membranes, omega-3 polyunsaturated fatty acids (n-3 PUFA) exhibit a wide range of regulatory functions. Recent human and animal studies indicate that n-3 PUFA may exert beneficial effects on aging processes. Here we analyzed the neuroprotective influence of n-3 PUFA supplementation on behavioral deficits, hippocampal neurogenesis, volume loss, and astrogliosis in aged mice that underwent a selective depletion of basal forebrain cholinergic neurons. Such a lesion represents a valid model to mimic a key component of the cognitive deficits associated with dementia. Aged mice were supplemented with n-3 PUFA or olive oil (as isocaloric control) for 8 weeks and then cholinergically depleted with mu-p75-saporin immunotoxin. Two weeks after lesioning, mice were behaviorally tested to assess anxious, motivational, social, mnesic, and depressive-like behaviors. Subsequently, morphological and biochemical analyses were performed. In lesioned aged mice the n-3 PUFA pre-treatment preserved explorative skills and associative retention memory, enhanced neurogenesis in the dentate gyrus, and reduced volume and VAChT levels loss as well as astrogliosis in hippocampus. The present findings demonstrating that n-3 PUFA supplementation before cholinergic depletion can counteract behavioral deficits and hippocampal neurodegeneration in aged mice advance a low-cost, non-invasive preventive tool to enhance life quality during aging.

Childcare programs often include mandatory naptime during the day. Loss of daytime sleep could lead to a moderate-to-large decrease in self-regulation, emotion processing, and learning in early childhood. Nevertheless, daytime sleep has been less accurately studied than nighttime sleep. This study aims to explore the relationship between diurnal sleep habits in nursery settings, nocturnal sleep quality, and post-nap emotional intensity in infants and toddlers.

Stiff Person Syndrome (SPS) is a rare autoimmune movement disorder characterized by the presence of autoantibodies specific to the smaller isoform of glutamate decarboxylase (GAD65). A pathological role of these antibodies has been suggested by their capacity to inhibit GAD65 enzyme activity and by the observation that rats receiving cerebellar injections of GAD65Ab showed cerebellar motor hyperexcitability. To assess the effect of epitope-specific GAD65Ab on cognitive and motor functions, we conducted behavioral experiments in rats that received cerebellar injections with two distinct monoclonal GAD65Ab (b96.11 and b78).

Environmental enrichment is usually applied immediately after weaning or in adulthood, with strong effects on CNS anatomy and behavior. To examine the hypothesis that a pre-reproductive environmental enrichment of females could affect the motor development of their offspring, female rats were reared in an enriched environment from weaning to sexual maturity, while other female rats used as controls were reared under standard conditions. Following mating with standard-reared males, all females were housed individually. To evaluate the eventual transgenerational influence of positive pre-reproductive maternal experiences, postural and motor development of male pups was analyzed from birth to weaning. Moreover, expression of Brain Derived Neurotrophic Factor and Nerve Growth Factor in different brain regions was evaluated at birth and weaning. Pre-reproductive environmental enrichment of females affected the offspring motor development, as indicated by the earlier acquisition of complex motor abilities displayed by the pups of enriched females. The earlier acquisition of motor abilities was associated with enhanced neurotrophin levels in striatum and cerebellum. In conclusion, maternal positive experiences were transgenerationally transmitted, and influenced offspring phenotype at both behavioral and biochemical levels.

Alterations of the dopaminergic (DAergic) system are frequently reported in Alzheimer's disease (AD) patients and are commonly linked to cognitive and non-cognitive symptoms. However, the cause of DAergic system dysfunction in AD remains to be elucidated. We investigated alterations of the midbrain DAergic system in the Tg2576 mouse model of AD, overexpressing a mutated human amyloid precursor protein (APPswe). Here, we found an age-dependent DAergic neuron loss in the ventral tegmental area (VTA) at pre-plaque stages, although substantia nigra pars compacta (SNpc) DAergic neurons were intact. The selective VTA DAergic neuron degeneration results in lower DA outflow in the hippocampus and nucleus accumbens (NAc) shell. The progression of DAergic cell death correlates with impairments in CA1 synaptic plasticity, memory performance and food reward processing. We conclude that in this mouse model of AD, degeneration of VTA DAergic neurons at pre-plaque stages contributes to memory deficits and dysfunction of reward processing.

Systemic inflammation might cause neuronal damage and sustain neurodegenerative diseases and behavior impairment, with the participation of pro-inflammatory cytokines, like tumor necrosis factor (TNF)-α and interleukin (IL)-18. However, the potential contribution of these cytokines to behavioral impairment in the long-term period has not been fully investigated.

Insomnia and circadian dysregulation during adolescence represent important risk factors for emotional and psychological problems. Recent studies have shown that the coronavirus disease 2019 (COVID-19) pandemic has been linked to a high prevalence of behavioural sleep problems in the general population. This study aimed to provide two pictures of two different time points of the pandemic regarding the prevalence of sleep problems in adolescents and their association with psychological health variables. Two different independent large samples of Italian adolescents aged 13-17 years were recruited at two pandemic time points. A total of 1,146 adolescents at Time 1 (T1; April 2020) and 1,406 at Time 2 (T2; April 2021) took part in the study. Measures of insomnia symptoms, sleep hygiene, chronotype, psychological distress and emotion regulation were collected. Prevalence of insomnia was 12.13% at T1 and 23.19% at T2. Furthermore, high levels of poor sleep habits (late bedtime, poor sleep hygiene, use of electronic devices at bedtime) were also detected at both time points. Insomnia symptoms strongly correlated with poor sleep hygiene, higher psychological distress, and emotional suppression at both time points. Results highlighted an alarming picture for two large samples at two different time points of the pandemic that showed a potential negative impact of the COVID-19 pandemic, in both the first outbreak and in the later phase of the pandemic, on sleep habits, psychological distress and insomnia symptoms in adolescents. This strongly suggests the need for monitoring these variables and their interaction in the post-pandemic period and to develop and promote interventions for insomnia and circadian disturbances during adolescence.

Cerebellar compensation is a reliable model of lesion-induced plasticity occurring through profound synaptic and neurochemical modifications in cortical and sub-cortical regions. As the recovery from cerebellar deficits progresses, the firstly enhanced glutamate striatal transmission is then normalized. The time course of cerebellar compensation and the concomitant striatal modifications might be influenced by protocols of environmental enrichment (EE) differently timed in respect to cerebellar lesion. In the present study, we analyzed the effects of different EE protocols on postural and locomotor behaviors (by means of a neurological rating scale), and on striatal synaptic activity (by means of recordings of spontaneous glutamate-mediated excitatory postsynaptic currents (sEPSCs)) and on morphological correlates (by means of density and dendritic length of Fast Spiking (FS) interneurons) following hemicerebellectomy (HCb) in rats. Cerebellar motor deficits were reduced faster in the enriched animals in comparison to standard housed HCbed rats. The beneficial influence of EE was higher in the animals enriched before the HCb than in rats enriched only after the lesion. In parallel, the HCb-induced increase in striatal sEPSCs was not observed in rats enriched before HCb and attenuated in rats enriched after HCb. Furthermore, the EE prevented the shrinkage of dendritic arborization of FS striatal interneurons. Also this effect was more marked in animals enriched before than after the HCb. The exposure to EE exerted either neuro-protective or therapeutic actions on the cerebellar deficits. The experience-dependent changes of the synaptic and neuronal connectivity observed in the striatal neurons may represent one of the mechanisms through which the enrichment facilitates functional compensation following the cerebellar damage.

Intraparenchymal injections of the immunotoxin 192-IgG-saporin into medial septum and nucleus basalis magnocellularis causes a selective depletion of basal forebrain cholinergic neurons. Thus, it represents a valid model to mimic a key component of the cognitive deficits associated with aging and dementia. Here we administered donepezil, a potent acetylcholinesterase inhibitor developed for treating Alzheimer's disease, 15 days before 192-IgG-saporin injection, and thus we examined donepezil effects on neurodegeneration and cognitive deficits.

During the first years of life, parental sleep strongly depends on child's sleep quality. Poor parental sleep may relate to increased stress and negative mood. However, there is a lack of sleep studies focusing on all family members. This study aimed to investigate the relationship between sleep, mood, and stress in mothers, fathers and children.

In recent years, mechanistic, epidemiologic, and interventional studies have indicated beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) against brain aging and age-related cognitive decline, with the most consistent effects against Alzheimer's disease (AD) confined especially in the early or prodromal stages of the pathology. In the present study, we investigated the action of n-3 PUFA supplementation on behavioral performances and hippocampal neurogenesis, volume, and astrogliosis in aged mice subjected to a selective depletion of basal forebrain cholinergic neurons. Such a lesion represents a valuable model to mimic one of the most reliable hallmarks of early AD neuropathology.

Environmental enrichment (EE) is a widely used paradigm for investigating the influence of complex stimulations on brain and behavior. Here we examined whether pre-reproductive exposure to EE of female rats may influence their maternal care and offspring cognitive performances. To this aim, from weaning to breeding age enriched females (EF) were reared in enriched environments. Females reared in standard conditions were used as controls. At 2.5 months of age all females were mated and reared in standard conditions with their offspring. Maternal care behaviors and nesting activity were assessed in lactating dams. Their male pups were also behaviorally evaluated at different post-natal days (pnd). Brain BDNF, reelin and adult hippocampal neurogenesis levels were measured as biochemical correlates of neuroplasticity. EF showed more complex maternal care than controls due to their higher levels of licking, crouching and nest building activities. Moreover, their offspring showed higher discriminative (maternal odor preference T-maze, pnd 10) and spatial (Morris Water Maze, pnd 45; Open Field with objects, pnd 55) performances, with no differences in social abilities (Sociability test, pnd 35), in comparison to controls. BDNF levels were increased in EF frontal cortex at pups' weaning and in their offspring hippocampus at pnd 21 and 55. No differences in offspring reelin and adult hippocampal neurogenesis levels were found. In conclusion, our study indicates that pre-reproductive maternal enrichment positively influences female rats' maternal care and cognitive development of their offspring, demonstrating thus a transgenerational transmission of EE benefits linked to enhanced BDNF-induced neuroplasticity.

As major components of neuronal membranes, omega-3 polyunsaturated acids (n-3 PUFA) exhibit a wide range of regulatory functions, modulating from synaptic plasticity to neuroinflammation, from oxidative stress to neuroprotection. Recent human and animal studies indicated the n-3 PUFA neuroprotective properties in aging, with a clear negative correlation between n-3 PUFA levels and hippocampal deficits. The present multidimensional study was aimed at associating cognition, hippocampal neurogenesis, volume, neurodegeneration and metabolic correlates to verify n-3 PUFA neuroprotective effects in aging. To this aim 19 month-old mice were given n-3 PUFA mixture, or olive oil or no dietary supplement for 8 weeks during which hippocampal-dependent mnesic functions were tested. At the end of behavioral testing morphological and metabolic correlates were analyzed. n-3 PUFA supplemented aged mice exhibited better object recognition memory, spatial and localizatory memory, and aversive response retention, without modifications in anxiety levels in comparison to controls. These improved hippocampal cognitive functions occurred in the context of an enhanced cellular plasticity and a reduced neurodegeneration. In fact, n-3 PUFA supplementation increased hippocampal neurogenesis and dendritic arborization of newborn neurons, volume, neuronal density and microglial cell number, while it decreased apoptosis, astrocytosis and lipofuscin accumulation in the hippocampus. The increased levels of some metabolic correlates (blood Acetyl-L-Carnitine and brain n-3 PUFA concentrations) found in n-3 PUFA supplemented mice also pointed toward an effective neuroprotection. On the basis of the present results n-3 PUFA supplementation appears to be a useful tool in health promotion and cognitive decline prevention during aging.

Pre-reproductive environmental enrichment of female rats influences sensorimotor development and spatial behavior of the offspring, possibly through the changed maternal nurturing. Nevertheless, maternal care could be not the solely responsible for changing offspring developmental trajectories. To disentangle the specific contribution to the transgenerational inheritance of pre- and post-natal factors, a cross-fostering study was performed. Female rats were reared in an enriched environment from weaning to sexual maturity, while control female rats were reared under standard conditions. Following mating with standard-reared males, all females were housed individually. Immediately after delivery, in- or cross-fostering manipulations were performed so that any foster dams received pups born to another dam of the same (in-fostering) or the opposite (cross-fostering) pre-reproductive rearing condition. In lactating dams maternal care and nesting activities were assessed, while in their male pups spatial abilities were assessed through Morris Water Maze (MWM) test at post-natal day 45. Moreover, the expression of Brain-Derived-Neurotrophic-Factor (BDNF) was evaluated in the hippocampus and frontal cortex of dams and pups at weaning. Pre-reproductive maternal environmental enrichment, followed by adoption procedures, loosened its potential in modifying maternal care and offspring developmental trajectories, as indicated by the lack of differences between in-fostered groups of dams and pups. In addition, enriched dams rearing standard pups showed the least complex maternal repertoire (the highest sniffing duration and the lowest nest quality), and their pups showed a reduced spatial learning in the MWM. Nevertheless, pre-reproductive maternal enrichment kept influencing neurotrophic pattern, with enriched dams expressing increased frontal BDNF levels (regardless of the kind of fostered pups), and their offspring expressing increased hippocampal BDNF levels. The present findings enlighten the crucial importance of the early mother-pups interactions in influencing maternal care and offspring phenotype, with the enriched dam-standard pups couple resulting in the most maladaptive encounter. Our study thus sustains that the bidirectional interactions between mother and pups are able to deeply shape offspring phenotype.

Although aversive memory has been mainly addressed by analysing the changes occurring in average populations, the study of neuronal mechanisms of outliers allows understanding the involvement of individual differences in fear conditioning and extinction. We recently developed an innovative experimental model of individual differences in approach and avoidance behaviors, classifying the mice as Approaching, Balancing or Avoiding animals according to their responses to conflicting stimuli. The approach and avoidance behaviors appear to be the primary reactions to rewarding and threatening stimuli and may represent predictors of vulnerability (or resilience) to fear. We submitted the three mice phenotypes to Contextual Fear Conditioning. In comparison to Balancing animals, Approaching and Avoiding mice exhibited no middle- or long-term fear extinction. The two non-extinguishing phenotypes exhibited potentiated glutamatergic neurotransmission (spontaneous excitatory postsynaptic currents/spinogenesis) of pyramidal neurons of medial prefrontal cortex and basolateral amygdala. Basing on the a priori individuation of outliers, we demonstrated that the maintenance of aversive memories is linked to increased spinogenesis and excitatory signaling in the amygdala-prefrontal cortex fear matrix.

Since brain injuries in adulthood are a leading cause of long-term disabilities, the development of rehabilitative strategies able to impact on functional outcomes requires detailing adaptive neurobiological responses. Functional recovery following brain insult is mainly ascribed to brain neuroplastic properties although the close linkage between neuronal plasticity and functional recovery is not yet fully clarified. The present study analyzed the reactive responses of pre-cerebellar (inferior olive, lateral reticular nucleus and pontine nuclei) and deep cerebellar nuclei after a hemicerebellectomy, considering the great plastic potential of the cerebellar system in physiological and pathological conditions. The time course of the plastic reorganization following cerebellar lesion was investigated by monitoring the Growth Associated Protein-43 (GAP-43) immunoreactivity. The time course of recovery from cerebellar symptoms was also assessed to parallel behavioral and neurobiological parameters. A key role of GAP-43 in neuronal reactive responses was evidenced. Neurons that underwent an axotomy as consequence of the right hemicerebellectomy (neurons of left inferior olive, right lateral reticular nucleus and left pontine nuclei) exhibited enhanced GAP-43 immunoreactivity and cell death. As for the not-axotomized neurons, we found enhanced GAP-43 immunoreactivity only in right pontine nuclei projecting to the spared (left) hemicerebellum. GAP-43 levels augmented also in the three deep cerebellar nuclei of the spared hemicerebellum, indicating the ponto-cerebellar circuit as crucially involved in functional recovery. Interestingly, each nucleus showed a distinct time course in GAP-43 immunoreactivity. GAP-43 levels peaked during the first post-operative week in the fastigial and interposed nuclei and after one month in the dentate nucleus. These results suggest that the earlier plastic events of the fastigial and interposed nuclei were driving compensation of the elementary features of posture and locomotion, while the later plastic events of the dentate nucleus were mediating the recovered ability to flexibly adjust the locomotor plan.