Project description:Episodic memories formed during the first postnatal period are rapidly forgotten, a phenomenon known as 'infantile amnesia'. In spite of this memory loss, early experiences influence adult behavior, raising the question of which mechanisms underlie infantile memories and amnesia. Here we show that in rats an experience learned during the infantile amnesia period is stored as a latent memory trace for a long time; indeed, a later reminder reinstates a robust, context-specific and long-lasting memory. The formation and storage of this latent memory requires the hippocampus, follows a sharp temporal boundary and occurs through mechanisms typical of developmental critical periods, including the expression switch of the NMDA receptor subunits from 2B to 2A, which is dependent on brain-derived neurotrophic factor (BDNF) and metabotropic glutamate receptor 5 (mGluR5). Activating BDNF or mGluR5 after training rescues the infantile amnesia. Thus, early episodic memories are not lost but remain stored long term. These data suggest that the hippocampus undergoes a developmental critical period to become functionally competent.
Project description:Secondhand tobacco smoke exposure in pregnancy increases the risk of neurodevelopmental disorders. We evaluated in rats whether there is a critical period during which tobacco smoke extract (TSE) affects the development of acetylcholine and serotonin systems, prominent targets for adverse effects of nicotine and tobacco smoke. We simulated secondhand smoke exposure by administering TSE so as to produce nicotine concentrations one-tenth those in active smoking, with 3 distinct, 10-day windows: premating, early gestation or late gestation. We conducted longitudinal evaluations in multiple brain regions, starting in early adolescence (postnatal day 30) and continued to full adulthood (day 150). TSE exposure in any of the 3 windows impaired presynaptic cholinergic activity, exacerbated by a decrement in nicotinic cholinergic receptor concentrations. Although the adverse effects were seen for all 3 treatment windows, there was a distinct progression, with lowest sensitivity for premating exposure and higher sensitivity for gestational exposures. Serotonin receptors were also reduced by TSE exposure with the same profile: little effect with premating exposure, intermediate effect with early gestational exposure and large effect with late gestational exposure. As serotonergic circuits can offset the neurobehavioral impact of cholinergic deficits, these receptor changes were maladaptive. Thus, there is no single 'critical period' for effects of low-level tobacco smoke but there is differential sensitivity dependent upon the developmental stage at the time of exposure. Our findings reinforce the need to avoid secondhand smoke exposure not only during pregnancy, but also in the period prior to conception, or generally for women of childbearing age.
Project description:Vulnerability for anxiety and depressive disorders is thought to have origins in early life and is increasingly recognized to involve deficits in GABAergic neurotransmission. Mice that were rendered heterozygous for the ?2 subunit gene of GABA(A) receptors (GABA(A)Rs) show behavioral, cognitive, neuroendocrine and pharmacologic features expected of a mouse model of melancholic anxious depression, including reduced survival of adult-born hippocampal neurons. Here we embarked on elucidating the developmental substrate underlying this phenotype, focusing on the Elevated Plus Maze and Forced Swim Test as relevant behavioral paradigms. In a first series of experiments using hemizygous tamoxifen-induced genetic inactivation of a floxed ?2 genomic locus we show that reducing the gene dosage at postnatal days (P)13/14 but not P27/28 results in altered behavior in both of these tests in adulthood, reminiscent of the anxious-depressive phenotype previously described for global heterozygous mice. However, in contrast to global heterozygous mice, the behavioral changes induced by ?2 subunit knockdown at P13/14 occurred without changes in adult hippocampal neurogenesis, indicating that altered neurogenesis is not an absolute prerequisite for anxiety- and depression-related behavior in this model. In a separate series of experiments using a pharmacological approach, acute but transient potentiation of GABA(A)Rs with diazepam uncovered distinct developmental vulnerabilities for altered behavior in the Elevated Plus Maze and Forced Swim Test, respectively. Specifically, diazepam given during P10-16 but not during later weeks resulted in increased anxiety-like behavior in adulthood, while diazepam administered during P29-35 but not earlier nor later resulted in increased immobility behavior in adulthood. We conclude that anxiety-like behavior in the Elevated Plus Maze and behavioral despair-like immobility in the Forced Swim Test are controlled by separate postnatal critical periods characterized by distinct developmental sensitivity to manipulation of GABAergic transmission via ?2 subunit-containing GABA(A)Rs.
Project description:Few studies have assessed the effects of developmental methylmercury (MeHg) exposure on learning and memory at different ages. The possibility of the amelioration or worsening of the effects has not been sufficiently investigated. This study aimed to assess whether low-dose MeHg exposure in utero and during suckling induces differential disturbances in learning and memory of periadolescent and young adult rats. Four experimental groups of pregnant Sprague-Dawley rats were orally exposed to MeHg or vehicle from gestational day 5 to weaning: (1) control (vehicle), (2) 250 μg/kg/day MeHg, (3) 500 μg/kg/day MeHg, and (4) vehicle, and treated on the test day with MK-801 (0.15 mg/kg i.p.), an antagonist of the N-methyl D-aspartate receptor. The effects were evaluated in male offspring through the open field test, object recognition test, Morris water maze, and conditioned taste aversion. For each test and stage assessed, different groups of animals were used. MeHg exposure, in a dose-dependent manner, disrupted exploratory behaviour, recognition memory, spatial learning, and acquisition of aversive memories in periadolescent rats, but alterations were not observed in littermates tested in young adulthood. These results suggest that developmental low-dose exposure to MeHg induces age-dependent detrimental effects. The relevance of decreasing exposure to MeHg in humans remains to be determined.
Project description:Adult neural plasticity within the visual system remains controversial. Starkly opposing views still remain on the ability of the visual system to reorganize in adulthood. Most attempts have focused on testing reorganization upon central visual loss. However, central loss triggers immediate adaptive strategies such as the emergence of new retinal preferential fixation loci, which may preclude plasticity. Moreover, plasticity may be further reduced in later ageing periods. Here we addressed this issue by studying visual plasticity in a genetically determined retinal disorder, Retinitis Pigmentosa, in which peripheral visual loss emerges not long after the critical period, in teenage years. We performed a case-control study with one-to-one matching and used an artificial scotoma approach which carefully simulated the defective visual field of each RP patient on a normal-sighted control. We used as outcomes population receptive field measures to probe long-term plasticity using fMRI retinotopy. We found evidence for reorganization based on pRF size metrics and explained variance of reorganized visual field maps. In sum, visual cortical plasticity triggered by peripheral visual loss occurs beyond the critical period of visual maturation.
Project description:Cortical circuits in the brain are refined by experience during critical periods early in postnatal life. Critical periods are regulated by the balance of excitatory and inhibitory (E/I) neurotransmission in the brain during development. There is now increasing evidence of E/I imbalance in autism, a complex genetic neurodevelopmental disorder diagnosed by abnormal socialization, impaired communication, and repetitive behaviors or restricted interests. The underlying cause is still largely unknown and there is no fully effective treatment or cure. We propose that alteration of the expression and/or timing of critical period circuit refinement in primary sensory brain areas may significantly contribute to autistic phenotypes, including cognitive and behavioral impairments. Dissection of the cellular and molecular mechanisms governing well-established critical periods represents a powerful tool to identify new potential therapeutic targets to restore normal plasticity and function in affected neuronal circuits.
Project description:Horns, also known as headgear, are a unique structure of ruminants. As ruminants are globally distributed, the study of horn formation is critical not only for increasing our understanding of natural and sexual selection but also for the breeding of polled sheep breeds to facilitate modern sheep farming. Despite this, a significant number of the underlying genetic pathways in sheep horn remain unclear. In this study, to clarify the gene expression profile of horn buds and investigate the key genes in horn bud formation, RNA-sequencing (RNA-seq) technology was utilized to investigate differential gene expression in the horn buds and adjacent forehead skin of Altay sheep fetuses. There were only 68 differentially expressed genes (DEGs) identified, consisting of 58 up-regulated genes and 10 down-regulated genes. RXFP2 was differentially up-regulated in the horn buds and had the highest significance (p-value = 7.42 × 10-14). In addition, 32 DEGs were horn-related genes identified in previous studies, such as RXFP2, FOXL2, SFRP4, SFRP2, KRT1, KRT10, WNT7B, and WNT3. Further, Gene Ontology (GO) analysis showed that the DEGs were mainly enriched with regard to growth, development, and cell differentiation. Pathway analysis revealed that the Wnt signaling pathway may be responsible for horn development. Further, through combining the protein-protein interaction networks of the DEGs, it was found that the top five hub genes, namely, ACAN, SFRP2, SFRP4, WNT3, and WNT7B, were also associated with horn development. Our results suggest that only a few key genes, including RXFP2, are involved in bud formation. This study not only validates the expression of candidate genes identified at the transcriptome level in previous studies but also provides new possible marker genes for horn development, which may promote our understanding of the genetic mechanisms of horn formation.
Project description:The first several months of life are a critical period for neuronal plasticity in the visual cortex during which anatomic and physiological development depends on visual experience. In cats, electrophysiologically assessed neuronal plasticity is minimal until approximately 3 weeks, peaks at 5 weeks, gradually declines to low levels at 20 weeks, and disappears at approximately 1 year of age (Daw, 1994). Rearing in darkness slows the entire time course of this critical period, such that at 5 weeks of age, normal cats are more plastic than dark-reared cats, whereas at 20 weeks, dark-reared cats are more plastic (Mower, 1991; Beaver et al., 2001). Thus, a stringent criterion is that genes that are important for plasticity in visual cortex will show differences in expression between normal rearing and dark rearing that are of opposite direction in young versus older animals. The present study reports the identification by differential display PCR of Munc13-3, a mammalian homolog of the Caenorhabditis elegans "uncoordinated" gene (unc-13), as a candidate gene for critical-period neuronal plasticity, the expression of which is regulated according to this criterion specifically in visual cortex and not in frontal cortex. Other members of the Munc13 family (Munc13-1 and Munc13-2) do not meet this criterion in visual cortex, indicating that Munc13-3 is the only family member that is regulated by age and dark rearing in the same manner as physiological plasticity during the visual cortical critical period.
Project description:A common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene, a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met), is associated with alterations in brain anatomy and memory, but its relevance to clinical disorders is unclear. We generated a variant BDNF mouse (BDNF(Met/Met)) that reproduces the phenotypic hallmarks in humans with the variant allele. BDNF(Met) was expressed in brain at normal levels, but its secretion from neurons was defective. When placed in stressful settings, BDNF(Met/Met) mice exhibited increased anxiety-related behaviors that were not normalized by the antidepressant, fluoxetine. A variant BDNF may thus play a key role in genetic predispositions to anxiety and depressive disorders.