Genes Brain and Behavior最新文献

Duchenne muscular dystrophy is a severe neuromuscular disorder that is caused by mutations in the DMD gene, resulting in a disruption of dystrophin production. Next to dystrophin expression in the muscle, different isoforms of the protein are also expressed in the brain and lack of these isoforms leads to cognitive and behavioral deficits in patients. It remains unclear how the loss of the shorter dystrophin isoform Dp140 affects these processes. Using a variety of behavioral tests, we found that mdx and mdx^4cv mice (which lack Dp427 or Dp427 + Dp140, respectively) exhibit similar deficits in working memory, movement patterns and blood–brain barrier integrity. Neither model showed deficits in spatial learning and memory, learning flexibility, anxiety or spontaneous behavior, nor did we observe differences in aquaporin 4 and glial fibrillary acidic protein. These results indicate that in contrast to Dp427, Dp140 does not play a crucial role in processes of learning, memory and spontaneous behavior.

Aquaculturists use polyploid fish to maximize production albeit with some unintended consequences including compromised behaviors and physiological function. Given benefits of probiotic therapies (e.g., improved immune response, growth, and metabolism), we explored probiotic supplementation (mixture of Bifidobacterium, Lactobacillus, and Lactococcus), to overcome drawbacks. We first examined fish gut bacterial community composition using 16S metabarcoding (via principal coordinate analyses and PERMANOVA) and determined probiotics significantly impacted gut bacteria composition (p = 0.001). Secondly, we examined how a genomic disruptor (triploidy) and diet supplements (probiotics) impact gene transcription and behavioral profiles of hatchery-reared Chinook salmon (Oncorhynchus tshawytscha). Juveniles from four treatment groups (diploid-regular feed, diploid-probiotic feed, triploid-regular feed, and triploid-probiotic feed; n = 360) underwent behavioral assays to test activity, exploration, neophobia, predator evasion, aggression/sociality, behavioral sensitivity, and flexibility. In these fish, transcriptional profiles for genes associated with neural functions (neurogenesis/synaptic plasticity) and biomarkers for stress response and development (growth/appetite) were (i) examined across treatments and (ii) used to describe behavioral phenotypes via principal component analyses and general linear mixed models. Triploids exhibited a more active behavioral profile (p = 0.002), and those on a regular diet had greater Neuropeptide Y transcription (p = 0.02). A growth gene (early growth response protein 1, p = 0.02) and long-term neural development genes (neurogenic differentiation factor, p = 0.003 and synaptysomal-associated protein 25-a, p = 0.005) impacted activity and reactionary profiles, respectively. Overall, our probiotic treatment did not compensate for triploidy. Our research highlights novel applications of behavioral transcriptomics for identifying candidate genes and dynamic, mechanistic associations with complex behavioral repertoires.

Reading disorders (RD) are human-specific neuropsychological conditions associated with decoding printed words and/or reading comprehension. So far only a handful of candidate genes segregated in families and 42 loci from genome-wide association study (GWAS) have been identified that jointly provided little clues of pathophysiology. Leveraging human-specific genomic information, we critically assessed the RD candidates for the first time and found substantial human-specific features within. The GWAS candidates (i.e., population signals) were distinct from the familial counterparts and were more likely pleiotropic in neuropsychiatric traits and to harbor human-specific regulatory elements (HSREs). Candidate genes associated with human cortical morphology indeed showed human-specific expression in adult brain cortices, particularly in neuroglia likely regulated by HSREs. Expression levels of candidate genes across human brain developmental stages showed a clear pattern of uplifted expression in early brain development crucial to RD development. Following the new insights and loci pleiotropic in cognitive traits, we identified four novel genes from the GWAS sub-significant associations (i.e., FOXO3, MAPT, KMT2E and HTT) and the Semaphorin gene family with functional priors (i.e., SEMA3A, SEMA3E and SEMA5B). These novel genes were related to neuronal plasticity and disorders, mostly conserved the pattern of uplifted expression in early brain development and had evident expression in cortical neuroglial cells. Our findings jointly illuminated the association of RD with neuroglia regulation—an emerging hotspot in studying neurodevelopmental disorders, and highlighted the need of improving RD phenotyping to avoid jeopardizing future genetic studies of RD.

Winona C. Booher, Lucy A. Hall, Aimee L. Thomas, et al. Genes Brain Behav. 2021;e12730.

In the above article, incorrect versions of Figures 4 and 5 were published in error. In both figures, the Low Activity (dotted line) should be on top and the High Activity (solid line) should be on the bottom.

The correct figures are reproduced below.

We apologize for this error.

Steroid sulphatase (STS) cleaves sulphate groups from steroid hormones, and steroid (sulphate) levels correlate with mood and age-related cognitive decline. In animals, STS inhibition or deletion of the associated gene, enhances memory/neuroprotection and alters hippocampal neurochemistry. Little is known about the consequences of constitutive STS deficiency on memory-related processes in humans. We investigated self-reported memory performance (Multifactorial Memory Questionnaire), word-picture recall and recent mood (Kessler Psychological Distress Scale, K10) in adult males with STS deficiency diagnosed with the dermatological condition X-linked ichthyosis (XLI; n = 41) and in adult female carriers of XLI-associated genetic variants (n = 79); we compared results to those obtained from matched control subjects [diagnosed with ichthyosis vulgaris (IV, n = 98) or recruited from the general population (n = 250)]. Using the UK Biobank, we compared mood/memory-related neuroanatomy in carriers of genetic deletions encompassing STS (n = 28) and non-carriers (n = 34,522). We found poorer word-picture recall and lower perceived memory abilities in males with XLI and female carriers compared with control groups. XLI-associated variant carriers and individuals with IV reported more adverse mood symptoms, reduced memory contentment and greater use of memory aids, compared with general population controls. Mood and memory findings appeared largely independent. Neuroanatomical analysis only indicated a nominally-significantly larger molecular layer in the right hippocampal body of deletion carriers relative to non-carriers. In humans, constitutive STS deficiency appears associated with mood-independent impairments in memory but not with large effects on underlying brain structure; the mediating psychobiological mechanisms might be explored further in individuals with XLI and in new mammalian models lacking STS developmentally.

Gastroesophageal reflux disease (GERD) is associated with sleep disturbances. However, mechanisms underlying these interactions remain unclear. Male acute and chronic sleep deprivation (SD) mice were used for this study. Mice in the chronic SD group exhibited anxiety- and depression-like behaviors. We further performed high-throughput genome sequencing and bioinformatics analysis to screen for featured differentially expressed genes (DEGs) in the esophageal tissue. The acute SD group, comprised 25 DEGs including 14 downregulated and 11 upregulated genes. Compared with the acute SD group, more DEGs were present in the chronic SD group, with a total of 169 DEGs, including 88 downregulated and 81 upregulated genes. Some DEGs that were closely related to GERD and associated esophageal diseases were significantly different in the chronic SD group. Quantitative real-time polymerase chain reaction verified the downregulation of Krt4, Krt13, Krt15 and Calml3 and upregulation of Baxl1 and Per3. Notably, these DEGs are involved in biological processes, which might be the pathways of the neuroregulatory mechanisms of DEGs expression.

Opioid use disorder (OUD) is an ongoing public health concern in the United States, and relatively little work has addressed how genetic background contributes to OUD. Understanding the genetic contributions to oxycodone-induced analgesia could provide insight into the early stages of OUD development. Here, we present findings from a behavioral phenotyping protocol using several inbred strains from the Hybrid Rat Diversity Panel. Our behavioral protocol included a modified “up-down” von Frey procedure to measure inherent strain differences in the sensitivity to a mechanical stimulus on the hindpaw. We also performed the tail immersion assay, which measures the latency to display tail withdrawal in response to a hot water bath. Initial withdrawal thresholds were taken in drug-naïve animals to record baseline thermal sensitivity across the strains. Oxycodone-induced analgesia was measured after administration of oxycodone over the course of 2 h. Both mechanical and thermal sensitivity are shaped by genetic factors and display moderate heritability (h² = 0.23–0.40). All strains displayed oxycodone-induced analgesia that peaked at 15–30 min and returned to baseline by 2 h. There were significant differences between the strains in the magnitude and duration of their analgesic response to oxycodone, although the heritability estimates were quite modest (h² = 0.10–0.15). These data demonstrate that genetic background confers differences in mechanical sensitivity, thermal sensitivity, and oxycodone-induced analgesia.

Mutations in CHD8 are one of the highest genetic risk factors for autism spectrum disorder. Studies in mice that investigate underlying mechanisms have shown Chd8 haploinsufficient mice display some trait disruptions that mimic clinical phenotypes, although inconsistencies have been reported in some traits across different models on the same strain background. One source of variation across studies may be the impact of Chd8 haploinsufficiency on maternal-offspring interactions. While differences in maternal care as a function of Chd8 genotype have not been studied directly, a previous study showed that pup survival was reduced when reared by Chd8 heterozygous dams compared with wild-type (WT) dams, suggesting altered maternal care as a function of Chd8 genotype. Through systematic observation of the C57BL/6 strain, we first determined the impact of Chd8 haploinsufficiency in the offspring on WT maternal care frequencies across preweaning development. We next determined the impact of maternal Chd8 haploinsufficiency on pup care. Compared with litters with all WT offspring, WT dams exhibited less frequent maternal behaviors toward litters consisting of offspring with mixed Chd8 genotypes, particularly during postnatal week 1. Dam Chd8 haploinsufficiency decreased litter survival and increased active maternal care also during postnatal week 1. Determining the impact of Chd8 haploinsufficiency on early life experiences provides an important foundation for interpreting offspring outcomes and determining mechanisms that underlie heterogeneous phenotypes.

Absence seizures are characterized by brief lapses in awareness accompanied by a hallmark spike-and-wave discharge (SWD) electroencephalographic pattern and are common to genetic generalized epilepsies (GGEs). While numerous genes have been associated with increased risk, including some Mendelian forms with a single causal allele, most cases of GGE are idiopathic and there are many unknown genetic modifiers of GGE influencing risk and severity. In a previous meta-mapping study, crosses between transgenic C57BL/6 and C3HeB/FeJ strains, each carrying one of three SWD-causing mutations (Gabrg2^{tm1Spet(R43Q)}, Scn8a^8j or Gria4^spkw1), demonstrated an antagonistic epistatic interaction between loci on mouse chromosomes 2 and 7 influencing SWD. These results implicate universal modifiers in the B6 background that mitigate SWD severity through a common pathway, independent of the causal mutation. In this study, we prioritized candidate modifiers in these interacting loci. Our approach integrated human genome-wide association results with gene interaction networks and mouse brain gene expression to prioritize candidate genes and pathways driving variation in SWD outcomes. We considered candidate genes that are functionally associated with human GGE risk genes and genes with evidence for coding or non-coding allele effects between the B6 and C3H backgrounds. Our analyses output a summary ranking of gene pairs, one gene from each locus, as candidates for explaining the epistatic interaction. Our top-ranking gene pairs implicate microtubule function, cytoskeletal stability and cell cycle regulation as novel hypotheses about the source of SWD variation across strain backgrounds, which could clarify underlying mechanisms driving differences in GGE severity in humans.

Chronic alcohol exposure results in widespread dysregulation of gene expression that contributes to the pathogenesis of Alcohol Use Disorder (AUD). Long noncoding RNAs are key regulators of the transcriptome that we hypothesize coordinate alcohol-induced transcriptome dysregulation and contribute to AUD. Based on RNA-Sequencing data of human prefrontal cortex, basolateral amygdala and nucleus accumbens of AUD versus non-AUD brain, the human LINC01265 and its predicted murine homolog Gm41261 (i.e., TX2) were selected for functional interrogation. We tested the hypothesis that TX2 contributes to ethanol drinking and behavioral responses to ethanol. CRISPR/Cas9 mutagenesis was used to create a TX2 mutant mouse line in which 306 base-pairs were deleted from the locus. RNA analysis revealed that an abnormal TX2 transcript was produced at an unchanged level in mutant animals. Behaviorally, mutant mice had reduced ethanol, gaboxadol and zolpidem-induced loss of the righting response and reduced tolerance to ethanol in both sexes. In addition, a male-specific reduction in two-bottle choice every-other-day ethanol drinking was observed. Male TX2 mutants exhibited evidence of enhanced GABA release and altered GABA_A receptor subunit composition in neurons of the nucleus accumbens shell. In C57BL6/J mice, TX2 within the cortex was cytoplasmic and largely present in Rbfox3+ neurons and IBA1+ microglia, but not in Olig2+ oligodendrocytes or in the majority of GFAP+ astrocytes. These data support the hypothesis that TX2 mutagenesis and dysregulation impacts ethanol drinking behavior and ethanol-induced behavioral responses in mice, likely through alterations in the GABAergic system.