Genes Brain and Behavior最新文献

Neurodegeneration in Huntington disease (HD) contributes to dopaminergic system dysfunction via the loss of striatal medium spiny neurons expressing dopamine receptors. Given the key role for ascorbic acid (vitamin C) in dopamine synthesis and neurotransmission, we investigated whether mild cellular ascorbate deficiency accelerates dopaminergic dysfunction in the development of HD pathology and behavioral deficits. YAC128 mice expressing mutant human huntingtin were crossed with SVCT2^+/− mice, which carry a heterozygous knockout of the sodium-dependent vitamin C transporter, to generate mice with approximately 30% decreased neuronal vitamin C as well as progressive changes in dopamine signaling. Behavioral and neurochemical outcomes were assessed at early disease stages. At 14 and 20 weeks, YAC128 and SVCT2^+/− YAC128 mice showed similar deficits in grip strength, locomotor activity, and rotarod performance compared to controls, suggesting modest ascorbate deficiency did not accelerate motor phenotypes. Gene expression analysis revealed six significantly upregulated genes in the striatum of SVCT2^+/− YAC128 mice, including those involved in dopamine synthesis, packaging, and transport. Notably, striatal dopamine and serotonin and their metabolites were decreased in both single mutant mouse lines (YAC128 and SVCT2^+/−) but without a compounding effect of the double mutation (SVCT2^+/− YAC128). These results indicate that while moderate ascorbate deficiency may not worsen early behavioral phenotypes in the YAC128 model, it does impact dopamine system regulation at the molecular level. These findings highlight the potential importance of ascorbate in modifying disease progression and suggest that humans with HD, who cannot synthesize ascorbate, may be particularly vulnerable to vitamin C deficiency effects on dopamine dynamics.

Genetic variation in CACNA1C, which encodes the alpha-1 subunit of Ca_v1.2 L-type voltage-gated calcium channels, is strongly linked to risk for psychiatric disorders including schizophrenia, bipolar disorder, and major depression. Here we investigated the impact of mutations of one copy of Cacna1c (leading to low gene dosage of Cacna1c) on rats' hedonic responses to palatable sucrose (assessed using the analysis of consumption microstructure). In addition, we also investigated the effects of combining either juvenile or adult stress with the manipulation of Cacna1c. Across three experiments, Cacna1c^+/− rats displayed attenuated hedonic reactions to sucrose compared to wild-type littermate controls, despite the Cacna1c^+/− rats retaining sensitivity to sucrose concentration in terms of the amount of consumption. Unexpectedly, juvenile stress enhanced rather than reduced hedonic reactions to sucrose, while adult stress did not have clear hedonic effects. The effects of Cacna1c manipulation did not interact with either juvenile or adult stress. The fact that Cacna1c^+/− rats display a clear analogue of anhedonia—a reduction in the positive hedonic reactions normally elicited by highly palatable sucrose—a symptom observed trans-diagnostically across psychiatric disorders linked to CACNA1C, suggests this model may play a valuable role in the translational investigation of anhedonia.

Alcohol addiction is a widespread disease, and the exact causes and consequences are still not fully determined. Neurotransmitters and neuronal circuits are not only the target structure of alcohol and responsible for its direct effects but also play a central role in the development of addiction. A gene that has been linked to alcohol use disorder in recent studies is the ganglioside-induced differentiation-associated protein 1 (GDAP1) gene. The present study focuses on the hippocampus, a brain region particularly vulnerable to alcohol and rich in Gdap1 gene expression. Using an established drinking model, alcohol drinking behavior was induced in adult male Long Evans rats. After 6 weeks of voluntary alcohol intake, followed by 2 weeks of deprivation, the animals were divided into two groups based on the alcohol deprivation effect (ADE). Gdap1 gene expression was measured with real-time PCR in the hippocampus. Results reveal significantly decreased mRNA expression in the high ADE group compared to the low ADE group. This decrease was specifically detected within the cornu ammonis 3 (CA3) region. Gdap1 expression in this region also negatively correlated with ADE in all animals. Taken together, results indicate that Gdap1 might not only be associated with alcohol consumption but might even play a role in alcohol dependence.

Higher delay discounting (DD) (i.e., propensity to devalue larger, delayed rewards over immediate, smaller rewards) is a transdiagnostic marker underpinning multiple health behaviors. Although genetic influences account for some of the variability in DD among adults, less is known about the genetic contributors to DD among preadolescents. We examined whether polygenic scores (PGS) for DD, educational attainment, and behavioral traits (i.e., impulsivity, inhibition, and externalizing behavior) were associated with phenotypic DD among preadolescents. Participants included youth (N = 8982, 53% male) from the Adolescent Brain Cognitive Development Study who completed an Adjusting Delay Discounting Task at the 1-year follow-up and had valid genetic data. PGS for DD, educational attainment, impulsivity, inhibition, and externalizing behaviors were created based on the largest GWAS available. Separate linear mixed effects models were conducted in individuals most genetically similar to European (EUR; n = 4972), African (AFR; n = 1769), and Admixed American (AMR; n = 2241) reference panels. After adjusting for age, sex, income, and the top ten genetic ancestry principal components, greater PGS for DD and lower educational attainment (but not impulsivity, inhibition, or externalizing) were associated with higher rates of DD (i.e., preference for sooner, smaller rewards) in participants most genetically similar to EUR reference panels. Findings provide insight into the influence of genetic propensity for DD and educational attainment on the discounting tendencies of preadolescents, particularly those most genetically similar to European reference samples, thereby advancing our understanding of the etiology of choice behaviors in this population.

The fundamental skills for motor coordination and motor control emerge through development. Neurodevelopmental disorders such as developmental coordination disorder (DCD) lead to impaired acquisition of motor skills. This study investigated motor behaviors that reflect the core symptoms of human DCD through the use of BXD recombinant inbred strains of mice that are known to have divergent phenotypes in many behavioral traits, including motor activity. We sought to correlate behavior in basic motor control tasks with the known genotypes of these reference populations of mice using quantitative trait locus (QTL) mapping. We used 12 BXD strains with an average of 16 mice per group to assess the onset of reflexes during the early neonatal stage of life and differences in motor coordination using the tests for open field, rotarod, and gait behaviors during the adolescent/young adulthood period. Results indicated significant variability between strains in when neonatal reflexes appeared and significant strain differences for all measures of motor coordination. Five strains (BXD15, BXD27, BXD28, BXD75, BXD86) struggled with sensorimotor coordination as seen in gait analysis, rotarod, and open field, similar to human presentation of DCD. We identified three significant quantitative trait loci for gait on proximal Chr 3, Chr 4, and distal Chr 6. Based on expression, function, and polymorphism within the mapped QTL intervals, seven candidate genes (Gpr63, Spata5, Trpc3, Cntn6, Chl1, Grm7, Ogg1) emerged. This study offers new insights into mouse motor behavior, which promises to be a first murine model to explore the genetics and neural correlates of DCD.

Addiction vulnerability is associated with the tendency to attribute incentive salience to reward predictive cues. Both addiction and the attribution of incentive salience are influenced by environmental and genetic factors. To characterize the genetic contributions to incentive salience attribution, we performed a genome-wide association study (GWAS) in a cohort of 1596 heterogeneous stock (HS) rats. Rats underwent a Pavlovian conditioned approach task that characterized the responses to food-associated stimuli (“cues”). Responses ranged from cue-directed “sign-tracking” behavior to food-cup directed “goal-tracking” behavior (12 measures, SNP heritability: 0.051–0.215). Next, rats performed novel operant responses for unrewarded presentations of the cue using the conditioned reinforcement procedure. GWAS identified 14 quantitative trait loci (QTLs) for 11 of the 12 traits across both tasks. Interval sizes of these QTLs varied widely. Seven traits shared a QTL on chromosome 1 that contained a few genes (e.g., Tenm4, Mir708) that have been associated with substance use disorders and other psychiatric disorders in humans. Other candidate genes (e.g., Wnt11, Pak1) in this region had coding variants and expression-QTLs in mesocorticolimbic regions of the brain. We also conducted a Phenome-Wide Association Study (PheWAS) on addiction-related behaviors in HS rats and found that the QTL on chromosome 1 was also associated with nicotine self-administration in a separate cohort of HS rats. These results provide a starting point for the molecular genetic dissection of incentive motivational processes and provide further support for a relationship between the attribution of incentive salience and drug abuse-related traits.

Acute stress has enduring effects on the brain and motivated behavior across species. For example, acute stress produces persisting decreases in voluntary physical activity as well as molecular changes in the striatum, a brain region that regulates voluntary physical activity and other motivated behaviors. Microglia, the primary immune cells of the central nervous system, are positioned at the interface between neural responses to stress and neural coordination of voluntary activity in that they respond to stress, sense molecular changes in the striatum, and modulate neuronal activity. However, the role of striatal microglia in stress-induced long-term suppression of voluntary activity is unknown. Here, we employ single-nucleus RNA sequencing to investigate how stress and exercise impact the biology of microglia in the striatum. We find that striatal microglia display altered activation profiles 6 weeks after an acute stressor. Furthermore, we show that access to a running wheel is associated with an additional and distinct microglial activation profile characterized by upregulation of genes related to complement components and phagocytosis pathways. Finally, we find that distinct gene sets show expression changes associated with general access to a running wheel versus variation in running levels. Taken together, our results deepen our understanding of the diverse molecular states that striatal microglia assume in response to stress and exercise and suggest that microglia exhibit a broader range of functional states than previously thought.

The National Institute of Drug Abuse convened a panel of scientists with expertise in substance use disorders (SUD) and genetic methodologies primarily to determine the feasibility of performing whole genome sequencing utilizing existing pedigree collections with a high density of SUD and psychiatric disorders. A major focus was on determining if there had been any successes in identifying genetic variants for complex traits in family-based designs. Such information could provide assurance that whole genome sequencing might provide significant pay-offs particularly in the pursuit of rare variants and copy number variants. An important goal was to discuss and evaluate optimal strategies for studying genetic variants in human samples. Specific topics were (a) to consider whether a smaller number of cases typically available in family studies versus the larger number available in biobanks can reveal unique information; (b) to identify potential gaps in information available in biobank data that might be supplemented with family data; (c) to consider the optimal SUD phenotypic definitions (e.g., quantity of use, problem-oriented) and data collection instruments (self-report or clinician administered) that are both practical and efficient to collect, and likely to provide important insights concerning prevention, intervention, and medication development. Conclusions reached by the panel included optimism about the successes that have occurred in the existing family studies ascertained to include densely affected pedigrees. Evaluation of methodologies led, overall, to a panel consensus that steps should be taken to utilize biobank collection in conjunction with family-based investigations for optimal variant discovery.

Sleep is of vital importance in our lives, yet we are far from understanding the neuronal networks that control the amount and timing of sleep. There is substantial conservation of known sleep-regulating transmitters, allowing for studies in simpler organisms to lead the way in gaining insight into the organization of sleep control circuits. In Drosophila melanogaster, we recently showed that optogenetic activation of neurons that produce the neuropeptide Y (NPY)-related transmitter short neuropeptide F (sNPF) increases time spent asleep. However, sNPF is expressed in several neuronal populations, and thus it is unknown which of those populations play roles in the sleep-promoting effect. In this study, we addressed this issue using a genetic approach to limit optogenetic activation to subsets of sNPF-expressing neurons. We found that sleep promotion was shorter-lived when cryptochrome (CRY)-positive neurons were excluded from being activated. Pigment-dispersing factor (PDF) neurons were not required for sleep promotion, nor were mushroom body (MB) neurons. Acute reactions to a short, 10-s period of optogenetic activation were largely unchanged by excluding activation of the three neuronal populations mentioned above. Together, these results suggest that clock neurons that are CRY-positive and PDF-negative are important contributors to the long-lasting sleep promotion produced by sNPF neuron activation. However, other neurons targeted by the sNPF-GAL4 driver appear to mediate the more rapid behavioral responses. Future studies will seek to identify these additional sNPF neuron populations and to determine how sNPF-expressing clock neurons act in concert with other neuronal circuits to promote sleep.

Recent theories suggest that reduced serotonin transporter (5-HTT) function, which increases serotonin (5-HT) levels at the synapse, enhances neural plasticity and affects sensitivity to environmental cues. This may promote learning about emotionally relevant events. However, the boundaries that define such emotional learning remain to be established. This was investigated using 5-HTT knockout (5-HTTKO) mice which provide a model of long-term elevated 5-HT transmission and are associated with increased anxiety. Compared to wild-type controls, 5-HTTKO mice were faster to discriminate between an auditory cue that predicted footshock (CS+) and a cue predicting no footshock (CS−). Notably, this enhanced discrimination performance was driven not by faster learning that the CS+ predicted footshock, but rather by faster learning that the CS− cue signals the absence of footshock and thus provides temporary relief from fear/anxiety. Similarly, 5-HTTKO mice were also faster to reduce their fear of the CS+ cue during subsequent extinction. These findings are consistent with facilitated inhibitory learning that predicts the absence of potential threats in 5-HTTKO mice. However, 5-HTTKO mice also exhibited increased generalisation of fear learning about ambiguous aversive cues in a novel context, different from the training context. Thus, 5-HTTKO mice can exhibit both more and less fear compared to wild-type controls. Taken together, our results support the idea that loss of 5-HTT function, and corresponding increases in synaptic 5-HT availability, may facilitate learning by priming of aversive memories. This both facilitates inhibitory learning for fear memories but also enhances generalisation of fear.