Cerebellar BDNF Promotes Exploration and Seeking for Novelty.

Background: Approach system considered a motivational system that activates reward-seeking behavior is associated with exploration/impulsivity, whereas avoidance system considered an attentional system that promotes inhibition of appetitive responses is associated with active overt withdrawal. Approach and avoidance dispositions are modulated by distinct neurochemical profiles and synaptic patterns. However, the precise working of neurons and trafficking of molecules in the brain activity predisposing to approach and avoidance are yet unclear. Methods: In 3 phenotypes of inbred mice, avoiding, balancing, and approaching mice, selected by using the Approach/Avoidance Y-maze, we analyzed endogenous brain levels of brain derived neurotrophic factor, one of the main secretory proteins with pleiotropic action. To verify the effects of the acute increase of brain derived neurotrophic factor, balancing and avoiding mice were bilaterally brain derived neurotrophic factor-infused in the cortical cerebellar regions. Results: Approaching animals showed high levels of explorative behavior and response to novelty and exhibited higher brain derived neurotrophic factor levels in the cerebellar structures in comparison to the other 2 phenotypes of mice. Interestingly, brain derived neurotrophic factor-infused balancing and avoiding mice significantly increased their explorative behavior and response to novelty. Conclusions: Cerebellar brain derived neurotrophic factor may play a role in explorative and novelty-seeking responses that sustain the approach predisposition.

The Complex Relationship between Sleep and Cognitive Reserve: A Narrative Review Based on Human Studies.

Sleep and brain/cognitive/neural reserve significantly impact well-being and cognition throughout life. This review aims to explore the intricate relationship between such factors, with reference to their effects on human cognitive functions. The specific goal is to understand the bidirectional influence that sleep and reserve exert on each other. Up to 6 February 2024, a methodical search of the literature was conducted using the PubMed database with terms related to brain, cognitive or neural reserve, and healthy or disturbed sleep. Based on the inclusion criteria, 11 articles were selected and analyzed for this review. The articles focus almost exclusively on cognitive reserve, with no explicit connection between sleep and brain or neural reserve. The results evidence sleep's role as a builder of cognitive reserve and cognitive reserve's role as a moderator in the effects of physiological and pathological sleep on cognitive functions. In conclusion, the findings of the present review support the notion that both sleep and cognitive reserve are critical factors in cognitive functioning. Deepening comprehension of the interactions between them is essential for devising strategies to enhance brain health and resilience against age- and pathology-related conditions.

Glucocorticoid receptor gene (NR3C1) methylation during the first thousand days: Environmental exposures and developmental outcomes.

The first 1000 days from conception are a sensitive period for human development programming. During this period, environmental exposures may result in long-lasting epigenetic imprints that contribute to future developmental trajectories. The present review reports on the effects of adverse and protective environmental conditions occurring during the first 1000 days on glucocorticoid receptor gene (NR3C1) regulation in humans. Thirty-four studies were included. Wide variations emerged for biological tissues, number and position of analyzed CpG sites, and age at methylation and outcomes assessment. Increased NR3C1 methylation associated with first 1000 days stress exposures. Maternal caregiving behaviors significantly buffered precocious stress exposures. A less robust pattern of findings emerged for the association of NR3C1 methylation with physical health, neurobehavioral and neuroendocrine outcomes. Although drawing comprehensive conclusions is partially hindered by methodological limitations, the present review underlines the relevance of the first 1000 days from conception as a time window for developmental plasticity. Prospective cohort studies and epigenome-wide approaches may increase our understanding of dynamics epigenetic changes and their consequences for child development.

Effects of pre-reproductive maternal enrichment on maternal care, offspring's play behavior and oxytocinergic neurons.

Potentiating social, cognitive, and sensorimotor stimulations the Environmental Enrichment (EE) increases levels of novelty and complexity experienced by individuals. Growing evidence demonstrates that parental EE experience, even occurring in the pre-reproductive phase, affects behavioral and neural developmental trajectories of the offspring. To discover how the accumulation of early maternal complex experiences may inform and shape the social behavior of the following generation, we examined the effects of pre-reproductive enrichment of dams (post-natal days 21-72) on the play performances of their male and female adolescent offspring. Furthermore, we examined the effects of pre-reproductive enrichment on maternal behavior (during post-partum days 1-10) and male intruder aggression (on post-partum day 11). Since oxytocin modulates maternal care, social bonding, and agonistic behavior, the number of oxytocinergic neurons of the paraventricular (PVN) and supraoptic (SON) nuclei was examined in both dams and offspring. Results revealed that enriched females exhibited higher levels of pup-oriented behaviors, especially Crouching, and initiated pup-retrieval more quickly than standard females after the maternal aggression test. Such behavioral peculiarities were accompanied by increased levels of oxytocinergic neurons in PVN and SON. Moreover, pre-reproductive maternal EE cross-generationally influenced the offspring according to sex. Indeed, male pups born to enriched females exhibited a reduced play fighting associated with a higher number of oxytocinergic neurons in SON in comparison to male pups born to standard-housed females. In conclusion, pre-reproductive EE to the mothers affects their maternal care and has a cross-generational impact on the social behavior of their offspring that do not directly experiences EE. This article is part of the Special Issue entitled "Neurobiology of Environmental Enrichment".

Pre-reproductive Parental Enriching Experiences Influence Progeny's Developmental Trajectories.

While the positive effects of environmental enrichment (EE) applied after weaning, in adulthood, during aging, or even in the presence of brain damage have been widely described, the transgenerational effects of pre-reproductive EE have been less examined. And yet, this issue is remarkable given that parental environmental experience may imprint offspring's phenotype over generations through many epigenetic processes. Interactions between individual and environment take place lifelong even before conception. In fact, the environment pre-reproductively experienced by the mother and/or the father exerts a substantial impact on neural development and motor and cognitive performances of the offspring, even if not directly exposed to social, cognitive, physical and/or motor enrichment. Furthermore, pre-reproductive parental enrichment exerts a transgenerational impact on coping response to stress as well as on the social behavior of the offspring. Among the effects of pre-reproductive parental EE, a potentiation of the maternal care and a decrease in global methylation levels in the frontal cortex and hippocampus of the progeny have been described. Finally, pre-reproductive EE modifies different pathways of neuromodulation in the brain of the offspring (involving brain-derived neurotrophic factor, oxytocin and glucocorticoid receptors). The present review highlights the importance of pre-reproductive parental enrichment in altering the performances not only of animals directly experiencing it, but also of their progeny, thus opening the way to new hypotheses on the inheritance mechanisms of behavioral traits.

Recovery of hippocampal functions and modulation of muscarinic response by electroacupuncture in young diabetic rats.

The muscarinic receptor response to acetylcholine regulates the hippocampal-related learning, memory, neural plasticity and the production and processing of the pro-nerve growth factor (proNGF) by hippocampal cells. The development and progression of diabetes generate a mild cognitive impairment reducing the functions of the septo-hippocampal cholinergic circuitry, depressing neural plasticity and inducing proNGF accumulation in the brain. Here we demonstrate, in a rat model of early type-1 diabetes, that a physical therapy, the electroacupuncture, counteracts the diabetes-induced deleterious effects on hippocampal physiology by ameliorating hippocampal-related memory functions; recovering the impaired long-term potentiation at the dentate gyrus (DG-LTP) and the lowered expression of the vesicular glutamate transporter 1; normalizing the activity-dependent release of proNGF in diabetic rat hippocampus. Electroacupuncture exerted its therapeutic effects by regulating the expression and activity of M1- and M2-acetylcholine muscarinic receptors subtypes in the dentate gyrus of hippocampus. Our results suggest that a physical therapy based on repetitive sensory stimulation could promote hippocampal neural activity, neuronal metabolism and functions, and conceivably improve the diabetes-induced cognitive impairment. Our data can support the setup of therapeutic protocols based on a better integration between physical therapies and pharmacology for the cure of diabetes-associated neurodegeneration and possibly for Alzheimer's disease.

Influence of Pre-reproductive Maternal Enrichment on Coping Response to Stress and Expression of c-Fos and Glucocorticoid Receptors in Adolescent Offspring.

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.