Genes Brain and Behavior最新文献

Neutral sphingomyelinase-2 (nSMase2), gene name sphingomyelin phosphodiesterase-3 (Smpd3), is a key regulatory enzyme responsible for generating the sphingolipid ceramide. The function of nSMase2 in the brain is still controversial. To better understand the functional roles of nSMase2 in the aging mouse brain, we applied RNA-seq analysis, which identified a total of 1462 differentially abundant mRNAs between +/fro and fro/fro, of which 891 were increased and 571 were decreased in nSMase2-deficient mouse brains. The most strongly enriched GO and KEGG annotation terms among transcripts increased in fro/fro mice included synaptogenesis, synapse development, synaptic signaling, axon development, and axonogenesis. Among decreased transcripts, enriched annotations included ribosome assembly and mitochondrial protein complex functions. KEGG analysis of decreased transcripts also revealed overrepresentation of annotations for Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington disease (HD). Ingenuity Pathway Analysis (IPA) tools predicted lower susceptibility to these neurodegenerative disorders, as well as predictions agreeing with stronger synaptic function, learning, and memory in fro/fro mice. The IPA tools identified signaling proteins, epigenetic regulators, and microRNAs as likely upstream regulators of the broader set of genes encoding the affected transcripts. It also revealed 16 gene networks, each linked to biological processes identified as overrepresented annotations among the affected transcripts by multiple analysis methods. Therefore, the analysis of these RNA-seq data indicates that nSMase2 impacts synaptic function and neural development, and may contribute to the onset and development of neurodegenerative diseases in middle-aged mice.

Repeated cocaine use produces adaptations in brain function that contribute to long-lasting behaviors associated with cocaine use disorder (CUD). In rodents, the activity-regulated cytoskeleton-associated protein (Arc) can regulate glutamatergic synaptic transmission, and cocaine regulates Arc expression and subcellular localization in multiple brain regions, including the nucleus accumbens (NAc)—a brain region linked to CUD-related behavior. We show here that repeated, non-contingent cocaine administration in global Arc KO male mice produced a dramatic hypersensitization of cocaine locomotor responses and drug experience-dependent sensitization of conditioned place preference (CPP). In contrast to the global Arc KO mice, viral-mediated reduction of Arc in the adult male, but not female, NAc (shArc^NAc) reduced both CPP and cocaine-induced locomotor activity, but without altering basal miniature or evoked glutamatergic synaptic transmission. Interestingly, cell type-specific knockdown of Arc in D1 dopamine receptor-expressing NAc neurons reduced cocaine-induced locomotor sensitization, but not cocaine CPP; whereas, Arc knockdown in D2 dopamine receptor-expressing NAc neurons reduced cocaine CPP, but not cocaine-induced locomotion. Taken together, our findings reveal that global, developmental loss of Arc produces hypersensitized cocaine responses; however, these effects cannot be explained by Arc's function in the adult mouse NAc since Arc is required in a cell type- and sex-specific manner to support cocaine-context associations and locomotor responses.

Delay discounting refers to the behavioral tendency to devalue rewards as a function of their delay in receipt. Heightened delay discounting has been associated with substance use disorders and multiple co-occurring psychopathologies. Human and animal genetic studies have established that delay discounting is heritable, but only a few associated genes have been identified. We aimed to identify novel genetic loci associated with delay discounting through a genome-wide association study (GWAS) using Heterogeneous Stock (HS) rats, a genetically diverse outbred population derived from eight inbred founder strains. We assessed delay discounting in 650 male and female HS rats using an adjusting amount procedure in which rats chose between smaller immediate sucrose rewards or a larger reward at various delays. Preference switch points were calculated and both exponential and hyperbolic functions were fitted to these indifference points. Area under the curve (AUC) and the discounting parameter k of both functions were used as delay discounting measures. GWAS for AUC, exponential k, and one indifference point identified significant loci on chromosomes 20 and 14. The gene Slc35f1, which encodes a member of the solute carrier family, was the sole gene within the chromosome 20 locus. That locus also contained an eQTL for Slc35f1, suggesting that heritable differences in the expression might be responsible for the association with behavior. Adgrl3, which encodes a latrophilin subfamily G-protein coupled receptor, was the sole gene within the chromosome 14 locus. These findings implicate novel genes in delay discounting and highlight the need for further exploration.

Rough-and-tumble play in juvenile rats and song in flocks of adult songbirds outside a breeding context (gregarious song) are two distinct forms of non-sexual social behavior. Both are believed to play roles in the development of sociomotor skills needed for later life-history events, including reproduction, providing opportunities for low-stakes practice. Additionally, both behaviors are thought to be intrinsically rewarded and are associated with a positive affective state. Given the functional similarities of these behaviors, this study used RNA-sequencing to identify commonalities in their underlying neurochemical systems within the medial preoptic area. This brain region is implicated in multiple social behaviors, including song and play, and is highly conserved across vertebrates. DESeq2 and rank–rank hypergeometric overlap analyses identified a shared neurotranscriptomic profile in adult European starlings singing high rates of gregarious song and juvenile rats playing at high rates. Transcript levels for several glutamatergic receptor genes, such as GRIN1, GRIN2A, and GRIA1, were consistently upregulated in highly gregarious (i.e., playful/high singing) animals. This study is the first to directly investigate shared neuromodulators of positive, non-sexual social behaviors across songbirds and mammals. It provides insight into a conserved brain region that may regulate similar behaviors across vertebrates.

Motherhood is a costly life-history transition accompanied by behavioral and neural plasticity necessary for offspring care. Motherhood in the monogamous prairie vole is associated with decreased pair bond strength, suggesting a trade-off between parental investment and pair bond maintenance. Neural mechanisms governing pair bonds and maternal bonds overlap, creating possible competition between the two. We measured mRNA expression of genes encoding receptors for oxytocin (oxtr), dopamine (d1r and d2r), mu-opioids (oprm1a), and kappa-opioids (oprk1a) within three brain areas processing salience of sociosensory cues (anterior cingulate cortex; ACC), pair bonding (nucleus accumbens; NAc), and maternal care (medial preoptic area; MPOA). We compared gene expression differences between pair bonded prairie voles that were never pregnant, pregnant (~day 16 of pregnancy), and recent mothers (day 3 of lactation). We found greater gene expression in the NAc (oxtr, d2r, oprm1a, and oprk1a) and MPOA (oxtr, d1r, d2r, oprm1a, and oprk1a) following the transition to motherhood. Expression for all five genes in the ACC was greatest for females that had been bonded for longer. Gene expression within each region was highly correlated, indicating that oxytocin, dopamine, and opioids comprise a complimentary gene network for social signaling. ACC-NAc gene expression correlations indicated that being a mother (oxtr and d1r) or maintaining long-term pair bonds (oprm1a) relies on the coordination of different signaling systems within the same circuit. Our study suggests the maternal brain undergoes changes that prepare females to face the trade-off associated with increased emotional investment in offspring, while also maintaining a pair bond.

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.