Deprivation-induced Changes Research Articles

Experience-dependent regulation of dopaminergic signaling in the somatosensory cortex

Dopamine critically influences reward processing, sensory perception, and motor control. Yet, the modulation of dopaminergic signaling by sensory experiences is not fully delineated. Here, by manipulating sensory experience using bilateral single-row whisker deprivation, we demonstrated that gene transcription in the dopaminergic signaling pathway (DSP) undergoes experience-dependent plasticity in both granular and supragranular layers of the primary somatosensory (barrel) cortex (S1). Sensory experience and deprivation compete for the regulation of DSP transcription across neighboring cortical columns, and sensory deprivation-induced changes in DSP are topographically constrained. These changes in DSP extend beyond cortical map plasticity and influence neuronal information processing. Pharmacological regulation of D2 receptors, a key component of DSP, revealed that D2 receptor activation suppresses excitatory neuronal excitability, hyperpolarizes the action potential threshold, and reduces the instantaneous firing rate. These findings suggest that the dopaminergic drive originating from midbrain dopaminergic neurons, targeting the sensory cortex, is subject to experience-dependent regulation and might create a regulatory feedback loop for modulating sensory processing. Finally, using topological gene network analysis and mutual information, we identify the molecular hubs of experience-dependent plasticity of DSP. These findings provide new insights into the mechanisms by which sensory experience shapes dopaminergic signaling in the brain and might help unravel the sensory deficits observed after dopamine depletion.

Leading basic modes of spontaneous activity drive individual functional connectivity organization in the resting human brain

Spontaneous activity of the human brain provides a window to explore intrinsic principles of functional organization. However, most studies have focused on interregional functional connectivity. The principles underlying rich repertoires of instantaneous activity remain largely unknown. We apply a recently proposed eigen-microstate analysis to three resting-state functional MRI datasets to identify basic modes that represent fundamental activity patterns that coexist over time. We identify five leading basic modes that dominate activity fluctuations. Each mode exhibits a distinct functional system-dependent coactivation pattern and corresponds to specific cognitive profiles. In particular, the spatial pattern of the first leading basis mode shows the separation of activity between the default-mode and primary and attention regions. Based on theoretical modelling, we further reconstruct individual functional connectivity as the weighted superposition of coactivation patterns corresponding to these leading basic modes. Moreover, these leading basic modes capture sleep deprivation-induced changes in brain activity and interregional connectivity, primarily involving the default-mode and task-positive regions. Our findings reveal a dominant set of basic modes of spontaneous activity that reflect multiplexed interregional coordination and drive conventional functional connectivity, furthering the understanding of the functional significance of spontaneous brain activity.

Phosphate deprivation-induced changes in tomato are mediated by an interaction between brassinosteroid signaling and zinc.

Inorganic phosphate (Pi) is a necessary macronutrient for basic biological processes. Plants modulate their root system architecture (RSA) and cellular processes to adapt to Pi deprivation albeit with a growth penalty. Excess application of Pi fertilizer, on the contrary, leads to eutrophication and has a negative environmental impact. We compared RSA, root hair elongation, acid phosphatase activity, metal ion accumulation, and brassinosteroid hormone levels of Solanum lycopersicum (tomato) and Solanum pennellii, which is a wild relative of tomato, under Pi sufficiency and deficiency conditions to understand the molecular mechanism of Pi deprivation response in tomato. We showed that S. pennellii is partially insensitive to phosphate deprivation. Furthermore, it mounts a constitutive response under phosphate sufficiency. We demonstrate that activated brassinosteroid signaling through a tomato BZR1 ortholog gives rise to the same constitutive phosphate deficiency response, which is dependent on zinc overaccumulation. Collectively, these results reveal an additional strategy by which plants can adapt to phosphate starvation.

Homeostatic regulation through strengthening of neuronal network-correlated synaptic inputs.

Homeostatic regulation is essential for stable neuronal function. Several synaptic mechanisms of homeostatic plasticity have been described, but the functional properties of synapses involved in homeostasis are unknown. We used longitudinal two-photon functional imaging of dendritic spine calcium signals in visual and retrosplenial cortices of awake adult mice to quantify the sensory deprivation-induced changes in the responses of functionally identified spines. We found that spines whose activity selectively correlated with intrinsic network activity underwent tumor necrosis factor alpha (TNF-α)-dependent homeostatic increases in their response amplitudes, but spines identified as responsive to sensory stimulation did not. We observed an increase in the global sensory-evoked responses following sensory deprivation, despite the fact that the identified sensory inputs did not strengthen. Instead, global sensory-evoked responses correlated with the strength of network-correlated inputs. Our results suggest that homeostatic regulation of global responses is mediated through changes to intrinsic network-correlated inputs rather than changes to identified sensory inputs thought to drive sensory processing.

Sleep Deprivation-Induced Changes in Baseline Brain Activity and Vigilant Attention Performance.

Sleep deprivation (SD) negatively affects several aspects of cognitive performance, and one of the most widely-used tools to evaluate these effects is the Psychomotor Vigilance Test (PVT). The present study investigated the possibility of predicting changes induced by SD in vigilant attention performance by evaluating the baseline electroencephalographic (EEG) activity immediately preceding the PVT stimuli onset. All participants (n = 10) underwent EEG recordings during 10 min of PVT before and after a night of SD. For each participant, the root mean square (RMS) of the baseline EEG signal was evaluated for each 1 s time window, and the respective average value was computed. After SD, participants showed slower (and less accurate) performance in the PVT task. Moreover, a close relationship between the changes in the baseline activity with those in cognitive performance was identified at several electrodes (Fp2, F7, F8, P3, T6, O1, Oz, O2), with the highest predictive power at the occipital derivations. These results indicate that vigilant attention impairments induced by SD can be predicted by the pre-stimulus baseline activity changes.

Impact of chronic sleep deprivation and sleep recovery on hippocampal oligodendrocytes, anxiety-like behavior, spatial learning and memory of rats

Sleep and its quality play an important role in memory, cognition, and quality of life. Sleep deprivation-induced changes in hippocampal neurons and behavior have been studied widely, in contrast, the extent of damage to oligodendrocytes have not been fully understood. The present study aims to investigate chronic sleep deprivation (CSD) and sleep recovery-induced changes in oligodendrocytes of the hippocampus, cognition, and behavior of rats. Male Sprague-Dawley rats (n = 48) were grouped as control, sham control (SC), CSD, and CSD+sleep recovery (CSD+SR) (n = 12/group). CSD and CSD+SR group rats were sleep deprived for 21-days. After CSD, the CSD+SR group rats sleep recovered for 21-days. Oxidative markers, CNPase+ve oligodendrocytes, CNPase intensity, and CNPase gene expression were measured in the hippocampus, and the anxiety-like behavior, spatial learning, and memory were assessed. The 21-days of CSD significantly (p < 0.001) increased oxidative stress and significantly (p < 0.001) reduced the number of CNPase+ve oligodendrocytes, CNPase intensity, and CNPase gene expression when compared to controls. The increased oxidative stress was correlated with reduced CNPase+ve oligodendrocytes, CNPase intensity, and CNPase gene expression (r = −0.9). In-line with cellular changes, an increased (p < 0.01) anxiety-like behavior and impaired spatial memory were observed in the CSD group compared to controls. The 21-days of sleep recovery significantly (p < 0.01) reduced oxidative stress and anxiety-like behavior, improved spatial memory, increased CNPase intensity and CNPase gene expression, and non-significant (p > 0.05) increase in CNPase+ve oligodendrocytes compared to CSD. Overall, the 21-days of CSD reduced the number of CNPase+ve oligodendrocytes in the hippocampus, increased anxiety, and impaired spatial memory in rats. Though the 21-day sleep recovery showed an improvement in all parameters, it was not sufficient to completely reverse the CSD-induced changes to the control level.

A genetic association study of tobacco withdrawal endophenotypes in African Americans.

Genome-wide association (GWA) genetic epidemiology research has identified several variants modestly associated with brief self-report smoking measures, predominately in European Americans. GWA research has not applied intensive laboratory-based measures of smoking endophenotypes in African Americans-a population with disproportionately low quit smoking rates and high tobacco-related disease risk. This genetic epidemiology study of non-Hispanic African Americans tested associations of 89 genetic variants identified in previous GWA research and exploratory GWAs with 24 laboratory-derived tobacco withdrawal endophenotypes. African American cigarette smokers (N = 528; ≥10 cig/day; 36.2% female) completed two counterbalanced visits following either 16-hr of tobacco deprivation or ad libitum smoking. At both visits, self-report and behavioral measures across six unique "sub-phenotype" domains within the tobacco withdrawal syndrome were assessed (Urge/Craving, Negative Affect, Low Positive Affect, Cognition, Hunger, and Motivation to Resume Smoking). Results of the candidate variant analysis found two significant small-magnitude associations. The rs11915747 alternate allele in the CAD2M gene region was associated with .09 larger deprivation-induced changes in reported impulsivity (0-4 scale). The rs2471711alternate allele in the AC097480.1/AC097480.2 gene region was associated with 0.26 lower deprivation-induced changes in confusion (0-4 scale). For both variants, associations were opposite in direction to previous research. Individual genetic variants may exert only weak influences on tobacco withdrawal in African Americans. Larger sample sizes of non-European ancestry individuals might be needed to investigate both known and novel loci that may be ancestry-specific. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Cortical Representation of Touch in Silico

With its six layers and ~ 12,000 neurons, a cortical column is a complex network whose function is plausibly greater than the sum of its constituents’. Functional characterization of its network components will require going beyond the brute-force modulation of the neural activity of a small group of neurons. Here we introduce an open-source, biologically inspired, computationally efficient network model of the somatosensory cortex’s granular and supragranular layers after reconstructing the barrel cortex in soma resolution. Comparisons of the network activity to empirical observations showed that the in silico network replicates the known properties of touch representations and whisker deprivation-induced changes in synaptic strength induced in vivo. Simulations show that the history of the membrane potential acts as a spatial filter that determines the presynaptic population of neurons contributing to a post-synaptic action potential; this spatial filtering might be critical for synaptic integration of top-down and bottom-up information.

Mechanism of Bruch's Membrane in the Occurrence and Development of Myopia

Myopia is a process of ocular wall remodeling along with axial elongation after emmetropia decompensation, but the causal relationship among the changes taking place in ocular fundus structures during this process is not clear. The choroid, which lies between the retina and the sclera, plays an important role in the transmission of information related to myopia. The role of choroid in myopia is a hot research topic at present. Findings from animal experiments showed that form deprivation-induced changes in choroidal thickness may be related to the vascular perfusion, but the triggering mechanism of choroidal perfusion changes during the process of myopia still needs to to be further explored. Bruch's membrane is an elastic membrane located in the front of the choroid with good contractile properties. In the process of myopia, regional changes of the synthesis or biomechanics of Bruch's membrane may have formed the earliest structural basis of changes in choroidal thickness and blood flow. Taking choroidal thickness as a starting point, this paper focuses on the role and mechanism of Bruch's membrane in the occurrence and development of myopia, which may further deepen our understanding of the mechanism of changes in choroidal thickness, and provide a theoretical basis for the development of new therapeutic targets for myopia.

Anhedonia in tobacco withdrawal among African-American smokers.

Anhedonia-diminished interest and pleasure in response to rewards-may be a symptom of tobacco withdrawal that is understudied in priority populations. This experiment investigated the magnitude and correlates of various dimensions of anhedonia during tobacco withdrawal among African-American (AA) smokers-a population subject to health disparities. AA smokers (N = 607; ≥ 10 cigarettes/day, 37.8% female, M[SD] age = 50.0[10.6] years) completed self-report measures assessing expected pleasure from (i.e., consummatory anhedonia) and desire to engage in (i.e., anticipatory anhedonia) various types of hypothetically experienced rewards at counterbalanced 16-hr tobacco deprived and nondeprived lab visits. Other tobacco withdrawal symptom measures (e.g., craving, negative affect, hunger) were also assessed. Tobacco deprivation most robustly increased scores on a composite measure of consummatory anhedonia directed toward various reward domains (i.e., hobbies, sensory experiences, social activities; d = .32, p < .001). Deprivation modestly increased consummatory and anticipatory anhedonia directed toward sexual rewards (ds = .09-.12, ps < .02), did not significantly change anhedonia toward food rewards, and decreased anhedonia directed toward psychoactive drug rewards (i.e., increased desire for and pleasure from drugs; ds = -.21 to -.19, ps < .001). Deprivation-induced changes in anhedonia were modestly correlated with other withdrawal symptoms (average |r|s = .04-.23) and were amplified among participants with higher nicotine dependence and lower positive affect-related traits (|β|s = .10-.12, ps < .01). Some dimensions of anhedonia may be genuine expressions of acute tobacco withdrawal in AA smokers. Applying multi-dimensional anhedonia conceptualizations might advance basic knowledge and treatment of tobacco use disorder, improve smoking cessation outcomes, and address tobacco-related health disparities facing AA smokers. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Exosomes derived from human induced pluripotent stem cell-derived neural progenitor cells protect neuronal function under ischemic conditions.

Compared with other stem cells, human induced pluripotent stem cells-derived neural progenitor cells (iPSC-NPCs) are more similar to cortical neurons in morphology and immunohistochemistry. Thus, they have greater potential for promoting the survival and growth of neurons and alleviating the proliferation of astrocytes. Transplantation of stem cell exosomes and stem cells themselves have both been shown to effectively repair nerve injury. However, there is no study on the protective effects of exosomes derived from iPSC-NPCs on oxygen and glucose deprived neurons. In this study, we established an oxygen-glucose deprivation model in embryonic cortical neurons of the rat by culturing the neurons in an atmosphere of 95% N2 and 5% CO2 for 1 hour and then treated them with iPSC-NPC-derived exosomes for 30 minutes. Our results showed that iPSC-NPC-derived exosomes increased the survival of oxygen- and glucose-deprived neurons and the level of brain-derived neurotrophic factor in the culture medium. Additionally, it attenuated oxygen and glucose deprivation-induced changes in the expression of the PTEN/AKT signaling pathway as well as synaptic plasticity-related proteins in the neurons. Further, it increased the length of the longest neurite in the oxygen- and glucose-deprived neurons. These findings validate the hypothesis that exosomes from iPSC-NPCs exhibit a neuroprotective effect on oxygen- and glucose-deprived neurons by regulating the PTEN/AKT signaling pathway and neurite outgrowth. This study was approved by the Animal Ethics Committee of Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, China (approval No. SRRSH20191010) on October 10, 2019.

Association of frequency of perceived exposure to discrimination with tobacco withdrawal symptoms and smoking lapse behavior in African Americans.

Frequent experiences of discrimination could increase vulnerability to tobacco withdrawal and smoking lapse in populations subject to tobacco-related health disparities. This laboratory study (2013-17) examined whether individual differences in perceived exposure to discrimination in one's daily life predicted tobacco withdrawal symptoms and smoking lapse behavior following acute tobacco deprivation in African American smokers. Mixed design with the between-subjects continuous variable of perceived discrimination crossed with the within-subject variable of tobacco deprivation status (deprived versus non-deprived). Academic medical center in Los Angeles, CA, USA. African American non-treatment seeking daily cigarette smokers (n=607, ≥10 cig/day). At a baseline visit, self-reported frequency of perceived exposure to discrimination in one's daily life was measured [everyday discrimination scale (EDDS)]. At two subsequent counterbalanced experimental visits (16-hour tobacco deprivation versus ad-libitum smoking), self-report assessments of various tobacco withdrawal symptom domains [Brief Questionnaire of Smoking Urges), Wisconsin Smoking Withdrawal Scale (WSWS), Profile of Mood States (POMS), Snaith-Hamilton Pleasure Scale (SHAPS) and Current Impulsivity Scale (CIS)) and a behavioral smoking lapse analogue task were measured. Adjusted models demonstrated that greater frequency of perceived exposure to discrimination was associated with larger deprivation-induced increases in acute urges to smoke to alleviate negative mood, several negative mood states and subjective cognitive functioning-effect sizes were small in magnitude (βs=0.09-0.13; Ps<0.02). Data were inconclusive for associations between perceived exposure to discrimination and deprivation-induced changes in cravings, urges to smoke for pleasure, positive mood reduction, other symptoms or smoking reinstatement behavior. Frequency of perceived exposure to discrimination appears to be modestly associated with increased severity of some deprivation-induced tobacco withdrawal symptoms in African American smokers.

Wistar rats and C57BL/6 mice differ in their motivation to seek social interaction versus food in the Social versus Food Preference Test

Here we characterized the Social versus Food Preference Test, a behavioral paradigm designed to investigate the competition between the choice to seek social interaction versus the choice to seek food. We assessed how this competition was modulated by internal cues (social isolation, food deprivation), external cues (stimulus salience), sex (males, females), age (adolescents, adults), and rodent model (Wistar rats, C57BL/6 mice). We found that changes in stimulus preference in response to the internal and external cue manipulations were similar across cohorts. Specifically, social over food preference scores were reduced by food deprivation and social familiarly in Wistar rats and C57BL/6 mice of both sexes. Interestingly, the degree of food deprivation-induced changes in stimulus investigation patterns were greater in adolescents compared to adults in Wistar rats and C57BL/6 mice. Strikingly, baseline stimulus preference and investigation times varied greatly between rodent models: across manipulations, Wistar rats were generally more social-preferring and C57BL/6 mice were generally more food-preferring. Adolescent Wistar rats spent more time investigating the social and food stimuli than adult Wistar rats, while adolescent and adult C57BL/6 mice investigated the stimuli a similar amount. Social isolation did not alter behavior in the Social versus Food Preference Test. Together, our results indicate that the Social versus Food Preference Test is a flexible behavioral paradigm suitable for future interrogations of the peripheral and central systems that can coordinate the expression of stimulus preference related to multiple motivated behaviors.

Prenatal and early postnatal food restrictions cause changes in brain oxidative status and orexigenic/anorexigenic hormones in the offspring of rats: prevention by quercetin and kaempferol

Brain oxidative signaling pathways have been identified as important targets for alleviating food deprivation-induced changes in metabolic gate-ways. Previous studies have shown that prenatal and early postnatal malnutrition alters leptin and ghrelin signaling via oxidative pathways. Thus, it has been hypothesized that agents with antioxidant properties might be beneficial for the mitigation of prenatal and early postnatal food scarcity-induced oxidative damage. Quercetin and kaempferol are natural bioflavonoids with proven antioxidant properties. In this study, we evaluated their effects on prenatal maternal food consumption, maternal and pup weights, biomarkers of orexigenic and anorexigenic hormones and oxidative stress in rats. Rats were allotted into different treatment groups (n ​= ​6) in three different experiments (prenatal, postnatal food-deprivations or both). Prenatal-food restriction (PrNFR) was induced by 50% of ad libitum accessible diet during pregnancy till parturition and postnatal-food restriction (PsNFR) was simulated by litter-enlargement to 16 pups per mother from postnatal day (PND) 2. Rats in each experiment were concurrently treated with vehicle (10 ​mL/kg), quercetin (50, 100 and 200 ​mg/kg, p.o.) or kaempferol (50, 100 and 200 ​mg/kg, p.o.) respectively. A third experimental group consisted of both protocols. Quercetin and kaempferol dose-dependently increased the body weights of pups exposed to PrNFR, PsNFR and PrNFR-PsNFR at PNDs 1–22 respectively. Both compounds increased maternal body weights but attenuated maternal food-intake at prenatal days 7 and 14 due by PrNFR. Quercetin and kaempferol reduced brain malondialdehyde concentrations and increased glutathione levels in PrNFR, PsNFR and PrNFR-PsNFR-exposed offspring of rats. Importantly, quercetin and kaempferol significantly (p ​< ​0.05) prevented PrNFR-, PsNFR- or PrNFR-PsNFR-induced alterations in leptin and ghrelin levels. Cumulatively, quercetin and kaempferol increased pup and maternal weights and attenuated maternal food-intake of rats submitted to PrNFR, PsNFR and PrNFR-PsNFR respectively, likely via nutrigenomic modulations of orexigenic/anorexigenic hormones and inhibition of brain oxidative stress.

Differential transcriptomic changes in low-potassium sensitive and low-potassium tolerant tea plant (Camellia sinensis) genotypes under potassium deprivation

Potassium (K) deficiency is a common abiotic stress that can inhibit plant growth and thus reduce crop productivity. K shortages in tea farms are very severe in current tea production systems. Therefore, developing low-K tolerant tea plants is an effective approach to mitigating K deficiencies in agricultural production systems. Up to now, the mechanisms underlying the transcriptional changes of tea plants under K+ deprivation have not been studied. In this study, to elucidate the underlying mechanism of tea plant genotype tolerance to K deprivation, we investigated K deprivation-induced changes in root morphology and global transcription in two tea plant genotypes, “1511″ and “1601″, which are tolerant and sensitive to low-K conditions, respectively. The results showed that the root systems were more developed in “1511″ than “1601″. The K starvation treatment increased the proportion of roots with a 0.5–2 mm diameter in “1511″ and the proportion of those with a 0–0.5 mm diameter in “1601″. There were 487 and 294 up-regulated genes in “1511″ and “1601″ (>2-fold change), respectively. The expression levels of the most differentially expressed genes in “1511″ were higher than those in “1601″. Under K+ starvation, we detected differentially expressed genes were only up-regulated in “1511″ associated with ethylene-related, ammonium transporter, nitrate transporter, catalase-related and phosphatidylinositol-related pathways. These up-regulated genes might play crucial roles in root architecture and K+ uptake and utilization, which would help enhance the low-K tolerance of “1511″. Our study provides new insights into the molecular mechanisms underlying tolerance of K+ starvation and builds a foundation for selecting low-K tolerance tea plant genotypes.

Temporary monocular occlusion facilitates binocular fusion during rivalry.

A few hours of monocular patching temporarily enhances the deprived eye's contribution to binocular vision, constituting a form of adult brain plasticity. Although the mechanism for this plasticity is currently unknown, several imaging studies present evidence that monocular deprivation achieves its effects by changing excitatory-inhibitory balance in the visual cortex. Much of the past work on adult monocular patching utilized binocular rivalry to quantify the patching-induced shift in perceptual eye dominance, extracting periods of exclusive visibility (in which one eye's signal is suppressed from perception) to assess each eye's contribution to binocular vision while overlooking the occurrence of mixed visibility (in which information from both eyes is combined). In this paper, we discuss two experiments to investigate the effects of short-term monocular occlusion on the relative predominance of mixed and exclusive percepts during binocular rivalry. In addition to the known perceptual eye-dominance shift, we hypothesized patching would also increase the perception of mixtures during rivalry due to deprivation-induced changes in excitatory-inhibitory balance. Our data point to two previously unknown effects of monocular deprivation: (a) a significant increase in the overall fraction and median duration of mixed visibility during rivalry that is detectable up to at least an hour after removing the patch and (b) the overall fraction of superimposition; rather than piecemeal, mixed percepts are specifically enhanced after monocular deprivation. In addition to strengthening the contribution of the deprived eye, our results show that temporary monocular patching enhances the visibility of fused binocular percepts, likely the result of attenuated interocular inhibition.

Retinoic Acid Receptor RARα-Dependent Synaptic Signaling Mediates Homeostatic Synaptic Plasticity at the Inhibitory Synapses of Mouse Visual Cortex.

Homeostatic synaptic plasticity is a synaptic mechanism through which the nervous system adjusts synaptic excitation and inhibition to maintain network stability. Retinoic acid (RA) and its receptor RARα have been established as critical mediators of homeostatic synaptic plasticity. In vitro studies reveal that RA signaling enhances excitatory synaptic strength and decreases inhibitory synaptic strength. However, it is unclear whether RA-mediated homeostatic synaptic plasticity occurs in vivo, and if so, whether it operates at specific types of synapses. Here, we examine the impact of RA/RARα signaling in the monocular zone of primary visual cortex (V1m) in mice of either sex. Exogenous RA treatment in acute cortical slices resulted in a reduction in mIPSCs of layer 2/3 pyramidal neurons, an effect mimicked by visual deprivation induced by binocular enucleation in postcritical period animals. Postnatal deletion of RARα blocked RA's effect on mIPSCs. Cell type-specific deletion of RARα revealed that RA acted specifically on parvalbumin (PV)-expressing interneurons. RARα deletion in PV+ interneurons blocked visual deprivation-induced changes in mIPSCs, demonstrating the critical involvement of RA signaling in PV+ interneurons in vivo Moreover, visual deprivation- or RA-induced downregulation of synaptic inhibition was absent in the visual cortical circuit of constitutive and PV-specific Fmr1 KO mice, strongly suggesting a functional interaction between fragile X mental retardation protein and RA signaling pathways. Together, our results demonstrate that RA/RARα signaling acts as a key component for homeostatic regulation of synaptic transmission at the inhibitory synapses of the visual cortex.SIGNIFICANCE STATEMENTIn vitro studies established that retinoic acid (RA) and its receptor RARα play key roles in homeostatic synaptic plasticity, a mechanism by which synaptic excitation/inhibition balance and network stability are maintained. However, whether synaptic RA signaling operates in vivo remains undetermined. Here, using a conditional RARα KO mouse and cell type-specific Cre-driver lines, we showed that RARα signaling in parvalbumin-expressing interneurons is crucial for visual deprivation-induced homeostatic synaptic plasticity at inhibitory synapses in visual cortical circuits. Importantly, this form of synaptic plasticity is absent when fragile X mental retardation protein is selectively deleted in parvalbumin-expressing interneurons, suggesting a functional connection between RARα and fragile X mental retardation protein signaling pathways in vivo Thus, dysfunction of RA-dependent homeostatic plasticity may contribute to cortical circuit abnormalities in fragile X syndrome.

Targeting histone deacetylation for recovery of maternal deprivation-induced changes in BDNF and AKAP150 expression in the VTA

Severe early life stressors increase the probability of developing psychiatric disorders later in life through modifications in neuronal circuits controlling brain monoaminergic signaling. Our previous work demonstrated that 24 h maternal deprivation (MD) in male Sprague Dawley rats modifies dopamine (DA) signaling from the ventral tegmental area (VTA) through changes at GABAergic synapses that were reversible by in vitro histone deacetylase (HDAC) inhibition which led to restoration of the scaffold A-kinase anchoring protein (AKAP150) signaling and subsequently recovered GABAergic plasticity (Authement et al., 2015). Using a combination of in situ hybridization, Western blots and immunohistochemistry, we confirmed that MD-induced epigenetic modifications at the level of histone acetylation were associated with an upregulation of HDAC2. MD also increased Akap5 mRNA levels in the VTA. Western blot analysis of AKAP150 protein expression showed an increase in synaptic levels of AKAP150 protein in the VTA with an accompanying decrease in synaptic levels of protein kinase A (PKA). Moreover, the abundance of mature brain-derived neurotrophic factor (BDNF) protein of VTA tissues from MD rats was significantly lower than in control groups. In vivo systemic injection with a selective class I HDAC inhibitor (CI-994) was sufficient to reverse MD-induced histone hypoacetylation in the VTA for 24 h after the injection. Furthermore, HDAC inhibition normalized the levels of mBDNF and AKAP150 proteins at 24 h. Our data suggest that HDAC-mediated targeting of BDNF and AKAP-dependent local signaling within VTA could provide novel therapeutics for prevention of later-life psychopathology.

Frontal metabolic activity contributes to individual differences in vulnerability toward total sleep deprivation-induced changes in cognitive function.

Substantial individual differences characterize the changes induced by total sleep deprivation on cognitive functions. Despite some progress having been achieved, the mechanisms of individual differences in response to total sleep deprivation have not been clearly elucidated. Cerebral metabolism in the resting state is among the key physiological processes supporting the daily function of the brain, and may play an important role in these individual differences. Twenty-two right-handed participants (nine females and 13 males) between 20 and 26years old completed a mathematical processing task both in resting wakefulness and after 24h of total sleep deprivation. Fluorine-18 fluorodeoxyglucose positron emission tomography-computed tomography was used to investigate brain metabolism changes. The mathematical task was performed after the positron emission tomography scans were completed. Correlation analysis was used to investigate the correlations between cognitive performance changes and brain metabolism changes. Large inter-individual differences were found in the throughput changes, but these inter-individual differences were not associated with baseline or post-deprivation performance levels. Specifically, deterioration of throughput on the mathematical processing task was significantly correlated with metabolism changes in the superior frontal medial gyrus. These findings suggested that frontal metabolic activity contributes to individual differences in waking-induced impairment of cognitive performance.

Hostility as a Predictor of Affective Changes During Acute Tobacco Withdrawal

Hostility--a personality trait reflective of cynical attitudes and a general mistrust of others--is associated with smoking status and relapse risk. Yet, the mechanisms linking hostility and smoking are not entirely clear. In this lab study, we tested a socioaffective model that purports that high-hostility individuals smoke to cope with maladaptive social mood states (i.e., anger and low friendliness), which become expressed and exacerbated during acute tobacco withdrawal. Following a baseline visit at which trait hostility was assessed, adult smokers (n = 153, ≥10 cig/day) attended two counterbalanced lab visits: a deprived session following 16 hr of deprivation, and a nondeprived session. At both lab visits, affect and withdrawal symptoms were assessed at a single time point. Higher trait hostility predicted larger deprivation-induced increases in several forms of negative affect (anxiety, depression, confusion; βs ≥ .20, ps ≤ .01) and a composite tobacco withdrawal symptom index (β = .16, p = .04) but did not predict changes in positive emotions. These effects persisted after statistically controlling for gender, nicotine dependence, and depression. Other aspects of trait aggression (i.e., verbal aggression, physical aggression, anger) did not predict deprivation-induced changes in affect and withdrawal other than state anger. High-hostility individuals appear to experience generalized exacerbations in several negative affective states during acute tobacco withdrawal. Increases in negative affect during tobacco withdrawal may motivate negative reinforcement-mediated smoking and could underlie tobacco addiction in high-hostility smokers.