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Role of RhoA/ROCK signaling in Alzheimer’s disease
RuoLanCaiabcdYangYangWangcdZhenTingHuangcdQianZoucdYinShuangPucdChangyinYubZhiyouCaicd
doi : 10.1016/j.bbr.2021.113481
Volume 414, 24 September 2021, 113481
Rho-associated coiled-coil kinase (ROCK), a serine/threonine kinase regulated by the small GTPase RhoA, is involved in regulating cell migration, proliferation, and survival. Numerous studies have shown that the RhoA/ROCK signaling pathway can promote Alzheimer's disease (AD) occurrence. ROCK activation increases ?-secretase activity and promotes amyloid-beta (A?) production; moreover, A? further activates ROCK. This is suggestive of a possible positive feedback role for A? and ROCK. Moreover, ROCK activation promotes the formation of neurofibrillary tangles and abnormal synaptic contraction. Additionally, ROCK activation can promote the neuroinflammatory response by activating microglia and astrocytes to release inflammatory cytokines. Therefore, ROCK is a promising drug target in AD; further, there is a need to elucidate the specific mechanism of action.
Paired associative stimulations: Novel tools for interacting with sensory and motor cortical plasticity
GiacomoGuidaliabCamillaRoncoronibNadiaBologninibc
doi : 10.1016/j.bbr.2021.113484
Volume 414, 24 September 2021, 113484
In the early 2000s, a novel non-invasive brain stimulation protocol, the paired associative stimulation (PAS), was introduced, allowing to induce and investigate Hebbian associative plasticity within the humans’ motor system, with patterns resembling spike-timing-dependent plasticity properties found in cellular models. Since this evidence, PAS efficacy has been proved in healthy, and to a lesser extent, in clinical populations. Recently, novel ‘modified’ protocols targeting sensorimotor and crossmodal networks appeared in the literature.
Metformin reduces oxandrolone- induced depression-like behavior in rats via modulating the expression of IL-1?, IL-6, IL-10 and TNF-?
Alaa M.HammadaYasmeen A.IbrahimaSawsan I.KhdairaF. ScottHallbMalekAlfarajaYazanJarraraAbdulqader FadhilAbeda
doi : 10.1016/j.bbr.2021.113475
Volume 414, 24 September 2021, 113475
Oxandrolone (OXA) is an androgen and anabolic steroid (AAS) that is used to reverse weight loss associated with some medical conditions. One of the side effects of OXA is its potential to induce depressive symptoms. Growing evidence suggested that neuroinflammation and cytokines play crucial roles in sickness behavioral and associated mood disturbances. Previous studies showed that metformin attenuated neuroinflammation. This study investigated the potential protective role of metformin against OXA-induced depression-like behavior and neuroinflammation. Twenty- four Wistar male rats were randomly grouped into four groups: the control group (Control) received only vehicle; the oxandrolone group (OXA) received oxandrolone (0.28?mg/kg, i.p); the metformin group (MET) received metformin (100?mg/kg, i.p); and the oxandrolone / metformin group (OXA?+?MET) received both oxandrolone (0.28?mg/kg, i.p) and metformin (100?mg/kg, i.p). These treatments were administered for fourteen consecutive days. Behavioral tests to measure depression-like behavior were conducted before and after treatments. qRT-PCR was used to measure the relative expression of proinflammatory and anti-inflammatory cytokines in the hippocampus and hypothalamus. The results showed that oxandrolone induced depression-like behavior and dysregulated pro-/anti-inflammatory cytokines, while metformin attenuated these effects. These findings suggest that metformin is a potential treatment to reverse the depressive effects induced by oxandrolone that involve neuroinflammatory effects.
Long-term high fat diet consumption reversibly alters feeding behavior via a dopamine-associated mechanism in mice
EverettAltherra1AundreaRainwatera1DarianKavianiaQijunTangaAli D.Gülerab
doi : 10.1016/j.bbr.2021.113470
Volume 414, 24 September 2021, 113470
Obesity is a costly, global epidemic that is perpetuated by an unhealthy diet. A significant factor in the initial consumption and maintenance of an unhealthy diet is the abundance of highly palatable, calorically dense foods. The aim of the present study is to better understand the effects of high fat diet (HFD) consumption on food valuation and preference, and to elucidate the neurobiological mechanisms mediating these effects. By using a novel food preference assay, we found that prolonged consumption of a HFD diminishes preference for and consumption of the more calorically dense food choice when two lab diets are presented. Additionally, we demonstrated that prolonged HFD consumption dampens ventral tegmental c-fos induction during hedonic feeding, implicating the mesolimbic dopamine signaling pathway as a target of HFD. Notably, both the changes in food preference and this reduced c-fos induction were reversed during withdrawal from HFD. Further, HFD-induced alterations in food preference were attenuated by exercise. Our findings suggest that prolonged HFD consumption leads to anhedonia and altered feeding choices, and this is associated with changes in mesolimbic dopamine signaling.
Is short-term memory capacity (7±2) really predicted by theta to gamma cycle length ratio?
Krist?naMalen?nsk?acd1VeronikaRudolfov?ab1Kate?ina?ulcov?aeVlastimilKoudelkaaMartinBrunovsk?aeJi??Hor??ekaeTerezaNekov??ov?ab
doi : 10.1016/j.bbr.2021.113465
Volume 414, 24 September 2021, 113465
Several studies suggest that EEG parameters, reflecting top-down processes in the brain, may predict cognitive performance, e.g. short-term memory (STM) capacity. According to Lisman and Idiart’s model, STM capacity is predicted by theta and gamma EEG waves and their ratio. This model suggests that the more periods of gamma band waves fit into one period of theta band waves, the more information can be stored. We replicated the study by Kaminski et al. (2011), which recorded spontaneous EEG activity and measured verbal STM capacity with a modified digit span task from the Wechsler battery. Our study included more subjects and two EEG recording sessions. We discuss the possible limits of EEG correlates of STM capacity as EEG parameters were not stable across the two measurements and no correlation was found between the theta/gamma ratio and performance in the digit span task.
Effects of transcranial random noise stimulation timing on corticospinal excitability and motor function
HarukiHoshiabShoKojimacNaofumiOtsurucHideakiOnishic
doi : 10.1016/j.bbr.2021.113479
Volume 414, 24 September 2021, 113479
Although transcranial random noise stimulation (tRNS) to the primary motor cortex (M1) increases corticospinal excitability and improves motor function, the effects of tRNS timing have not been clarified when combined with motor training. The purpose of this study was to clarify the effects of different tRNS timing on corticospinal excitability and motor function. We applied tRNS to the left M1 using a frequency of 0.1–640?Hz for 10?min to 15 healthy subjects. Subjects performed visuomotor tracking tasks with right hand for 10?min and participated in the following four conditions based on the timing of tRNS: (1) “before” condition, tRNS was performed before motor training; (2) “during” condition, tRNS was performed during motor training; (3) “after” condition, tRNS was performed after motor training; and (4) sham condition, the control group. Motor evoked potential (MEP) amplitudes were recorded from the right first dorsal interosseous muscle using transcranial magnetic stimulation. MEP amplitudes were assessed by baseline followed by three sessions at 10?min intervals. The motor function was assessed before and after tRNS and motor training. The MEP amplitude increased after tRNS in the before and during conditions but not in the after condition. Motor function after motor training improved in all conditions, but there were no significant differences between these conditions. The present study revealed that the timing of tRNS affects corticospinal excitability but not motor learning.
miR-142 downregulation alleviates the impairment of spatial learning and memory, reduces the level of apoptosis, and upregulates the expression of pCaMKII and BAI3 in the hippocampus of APP/PS1 transgenic mice
Chang-HaiFuaXue-YanHanbLeiTongaPeng-YinNieaYue-DongHucLi-LiJia
doi : 10.1016/j.bbr.2021.113485
Volume 414, 24 September 2021, 113485
MicroRNA-142-5p (miR-142-5p) has been found to be dysregulated in several neurodegenerative disorders. However, little is known about the involvement of miR-142-5p in Alzheimer’s disease (AD). Brain angiogenesis inhibitor 3 (BAI3), which belongs to the adhesion-G protein-coupled receptor subgroup, contributes to a variety of neuropsychiatric disorders. Despite its very high expression in neurons, the role of BAI3 in AD remains elusive, and its mechanism at the cellular and molecular levels needs to be further elucidated.
Circadian rhythm influences naloxone induced morphine withdrawal and neuronal activity of lateral paragigantocellularis nucleus
FatemehRahmati-DehkordiaMasoumehGhaemi-JandabiaBehzadGarmabibSaeedSemnanianacHosseinAziziac
doi : 10.1016/j.bbr.2021.113450
Volume 414, 24 September 2021, 113450
Investigations have shown that the circadian rhythm can affect the mechanisms associated with drug dependence. In this regard, we sought to assess the negative consequence of morphine withdrawal syndrome on conditioned place aversion (CPA) and lateral paragigantocellularis (LPGi) neuronal activity in morphine-dependent rats during light (8:00?12:00) and dark (20:00?24:00) cycles. Male Wistar rats (250?300 g) were received 10 mg/kg morphine or its vehicle (Saline, 2 mL/kg/12 h, s.c.) in 13 consecutive days for behavioral assessment tests. Then, naloxone-induced conditioned place aversion and physical signs of withdrawal syndrome were evaluated during light and dark cycles. In contrast to the behavioral part, we performed in vivo extracellular single-unit recording for investigating the neural response of LPGi to naloxone in morphine-dependent rats on day 10 of morphine/saline exposure. Results showed that naloxone induced conditioned place aversion in both light and dark cycles, but the CPA score during the light cycle was larger. Moreover, the intensity of physical signs of morphine withdrawal syndrome was more severe during the light cycle (rest phase) compare to the dark one. In electrophysiological experiments, results indicated that naloxone evoked both excitatory and inhibitory responses in LPGi neurons and the incremental effect of naloxone on LPGi activity was stronger in the light cycle. Also, the neurons with the excitatory response exhibited higher baseline activity in the dark cycle, but the neurons with the inhibitory response showed higher baseline activity in the light cycle. Interestingly, the baseline firing rate of neurons recorded in the light cycle was significantly different in response (excitatory/inhibitory) -dependent manner. We concluded that naloxone-induced changes in LPGi cellular activity and behaviors of morphine-dependent rats can be affected by circadian rhythm and the internal clock.
Information transmission in mPFC-BLA network during exploratory behavior in the open field
XuehuiBaoChengxiQiTiaotiaoLiuXuyuanZheng
doi : 10.1016/j.bbr.2021.113483
Volume 414, 24 September 2021, 113483
Exploratory behavior plays a fundamental role in motivation, learning, and well-being of organisms. The open field test (OFT) is a classic method to investigate the exploratory behavior in rodents, also a widely adopted and pharmacologically validated procedure for evaluating anxiety and depression. Several lines of evidence have shown that medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) play crucial roles in anxiety-like or depression-like exploratory behavior. However, the dynamic characterization of the mPFC-BLA network in exploratory behavior is less well understood. Therefore, this study aimed to investigate the information transmission mechanism in the mPFC-BLA network during exploratory behavior. Local field potentials (LFPs) from mPFC and BLA were simultaneously recorded while the rats performed the OFT. Directed transfer function (DTF), which was derived from Granger causal connectivity analysis, was applied to measure the functional connectivity among LFPs. Information flow (IF) was calculated to explore the dynamics of information transmission in the mPFC-BLA network. Our results revealed that, for both mPFC and BLA, the theta-band functional connectivity in periphery was significantly higher than that in center of the open field. The IF from BLA to mPFC in the open field task was significantly higher than that from mPFC to BLA. These results suggest that the functional connectivity and IF in the mPFC-BLA network are related to the exploratory behavior, and information transmission from BLA to mPFC could be predominant for exploratory behavior.
Transcranial Direct Current Stimulation (tDCS) over the Frontopolar Cortex (FPC) Alters the Demand for Precommitment
JinjinWangacYuzhenLibcSiqiWangcdWenminGuobcHangYebcJinchuanShiaJunLuobc
doi : 10.1016/j.bbr.2021.113487
Volume 414, 24 September 2021, 113487
Caving into temptation leads to deviation from the planned path, which reduces our performance, adds trouble to our daily life, and can even bring about psychiatric disorders. Precommitment is an effective way to remedy the failure of willpower by removing the tempting short-term option. This paper aims to test the neural mechanisms of precommitment through a monetary task that excluded the interference of heterogeneous individual preferences and complements present researches. We examined whether transcranial direct current stimulation (tDCS) over the frontopolar cortex (FPC) could affect the demand for precommitment. The participants were required to make a decision regarding whether they were willing to precommit to binding later-lar ger rewards and remove the sooner-smaller rewards. Three conditions, including no precommitment, loose precommitment and strict precommitment, were established to perform a comprehensive investigation. We found that tDCS over the FPC altered the demand for precommitment in the condition involving loose precommitment with the control of delay discounting, specifically, anodal stimulation led to more precommitment, whereas cathodal stimulation reduced the demand for precommitment. Our findings established a causal correlation between the FPC and willingness to precommit and suggested a feasible method to enhance self-control in addition to exercising willpower.
Heart failure impairs mood and memory in male rats and down-regulates the expression of numerous genes important for synaptic plasticity in related brain regions
Marise B.Parent1Hildebrando CandidoFerreira-Neto1Ana RafaelaKruemmel1FerdinandAlthammerAtit A.PatelSreinickKeoKathryn E.WhitleyDaniel N.CoxJavier E.Stern
doi : 10.1016/j.bbr.2021.113452
Volume 414, 24 September 2021, 113452
Chronic heart failure (HF) is a serious disorder that afflicts more than 26 million patients worldwide. HF is comorbid with depression, anxiety and memory deficits that have serious implications for quality of life and self-care in patients who have HF. Still, there are few studies that have assessed the effects of severely reduced ejection fraction (?40 %) on cognition in non-human animal models. Moreover, limited information is available regarding the effects of HF on genetic markers of synaptic plasticity in brain areas critical for memory and mood regulation. We induced HF in male rats and tested mood and anxiety (sucrose preference and elevated plus maze) and memory (spontaneous alternation and inhibitory avoidance) and measured the simultaneous expression of 84 synaptic plasticity-associated genes in dorsal (DH) and ventral hippocampus (VH), basolateral (BLA) and central amygdala (CeA) and prefrontal cortex (PFC). We also included the hypothalamic paraventricular nucleus (PVN), which is implicated in neurohumoral activation in HF. Our results show that rats with severely reduced ejection fraction recapitulate behavioral symptoms seen in patients with chronic HF including, increased anxiety and impaired memory in both tasks. HF also downregulated several synaptic-plasticity genes in PFC and PVN, moderate decreases in DH and CeA and minimal effects in BLA and VH. Collectively, these findings identify candidate brain areas and molecular mechanisms underlying HF-induced disturbances in mood and memory.
Loss of SUR1 subtype KATP channels alters antinociception and locomotor activity after opioid administration
GeraldSakamakiKaylaJohnsonMeganMensingerEindrayHmuAmanda H.Klein
doi : 10.1016/j.bbr.2021.113467
Volume 414, 24 September 2021, 113467
Opioid signaling can occur through several downstream mediators and influence analgesia as well as reward mechanisms in the nervous system. KATP channels are downstream targets of the ? opioid receptor and contribute to morphine-induced antinociception. The aim of the present work was to assess the role of SUR1-subtype KATP channels in antinociception and hyperlocomotion of synthetic and semi-synthetic opioids. Adult male and female mice wild-type (WT) and SUR1 deficient (KO) mice were assessed for mechanical and thermal antinociception after administration of either buprenorphine, fentanyl, or DAMGO. Potassium flux was assessed in the dorsal root ganglia and superficial dorsal horn cells in WT and KO mice. Hyperlocomotion was also assessed in WT and KO animals after buprenorphine, fentanyl, or DAMGO administration. SUR1 KO mice had attenuated mechanical antinociception after systemic administration of buprenorphine, fentanyl, and DAMGO. Potassium flux was also attenuated in the dorsal root ganglia and spinal cord dorsal horn cells after acute administration of buprenorphine and fentanyl. Hyperlocomotion after administration of morphine and buprenorphine was potentiated in SUR1 KO mice, but was not seen after administration of fentanyl or DAMGO. These results suggest SUR1-subtype KATP channels mediate the antinociceptive response of several classes of opioids (alkaloid and synthetic/semi-synthetic), but may not contribute to the “drug-seeking” behaviors of all classes of opioids.
Differential expression of H19, BC1, MIAT1, and MALAT1 long non-coding RNAs within key brain reward regions after repeated morphine treatment
ShamseddinAhmadiaMohammadZobeiriaShivaMohammadi TalvaraKayvanMasoudiaAmirKhanizadaShimaFotouhiaStevenBradburnb
doi : 10.1016/j.bbr.2021.113478
Volume 414, 24 September 2021, 113478
Morphine-induced analgesic tolerance and dependence are significant limits of pain control; however, the exact molecular mechanisms underlying morphine tolerance and dependence have remained unclear. The role of long non-coding RNAs (lncRNAs) in morphine tolerance and dependence is yet to be determined. We aimed to explore the association of specific lncRNAs expression in key brain reward regions after repeated injection of morphine. Male Wistar rats received subcutaneous injections of twice-daily morphine (10 mg/kg) or saline (1 mL/kg) for eight days. On day 8 of the repeated injections, induction of morphine analgesic tolerance and dependence was confirmed through a hotplate test and a naloxone-precipitated withdrawal analysis, respectively. Expression of H19, BC1, MIAT1, and MALAT1 lncRNAs was determined from the midbrain, striatum, hypothalamus, prefrontal cortex (PFC), and hippocampus by real-time PCR on day 8 of the repeated injections. The H19 expression was significantly different between morphine-treated and control saline-treated rats in all investigated areas except for the hippocampus. The BC1 expression significantly altered in the midbrain, hypothalamus, and hippocampus, but not in the striatum and PFC after repeated morphine treatment. The MIAT1 and MALAT1 expression site-specifically altered in the midbrain, hypothalamus, and striatum; however, no significant changes were detected in their expression in the PFC and hippocampus after repeated morphine treatment. We conclude that alterations in the expression of these lncRNAs in the brain reward regions especially in the midbrain, striatum and hypothalamus may have critical roles in the development of morphine dependence and tolerance, which need to be considered in future researches.
Effect of histone acetylation on maintenance and reinstatement of morphine-induced conditioned place preference and ?FosB expression in the nucleus accumbens and prefrontal cortex of male rats
HashemSaberianaAfsanehAsgari TaeiaAnahitaTorkaman-BoutorabiaEsmailRiahibSamanehAminyavariaAyehNaghizadehcMaryamFarahmandfara
doi : 10.1016/j.bbr.2021.113477
Volume 414, 24 September 2021, 113477
Recently, epigenetic mechanisms are considered as the new potential targets for addiction treatment. This research was designed to explore the effect of histone acetylation on ?FosB gene expression in morphine-induced conditioned place preference (CPP) in male rats. CPP was induced via morphine injection (5?mg/kg) for three consecutive days. Animals received low-dose theophylline (LDT) or Suberoylanilide Hydroxamic acid (SAHA), as an histone deacetylase (HDAC) activator or inhibitor, respectively, and a combination of both in subsequent extinction days. Following extinction, a priming dose of morphine (1?mg/kg) was administered to induce reinstatement. H4 acetylation and ?FosB expression in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) were assessed on the last day of extinction and the following CPP reinstatement. Our results demonstrated that daily administration of SAHA (25?mg/kg; i.p.), facilitated morphine-extinction and decreased CPP score in reinstatement of place preference. Conversely, injections of LDT (20?mg/kg; i.p.) prolonged extinction in animals. Co-administration of LDT and SAHA on extinction days counterbalanced each other, such that maintenance and reinstatement were no different than the control group. The gene expression of ?FosB was increased by SAHA in NAc and mPFC compared to the control group. Administration of SAHA during extinction days, also altered histone acetylation in the NAc and mPFC on the last day of extinction, but not on reinstatement day. Collectively, administration of SAHA facilitated extinction and reduced reinstatement of morphine-induced CPP in rats. This study confirms the essential role of epigenetic mechanisms, specifically histone acetylation, in regulating drug-induced plasticity and seeking behaviors.
Neuroplasticity induced by the retention period of a complex motor skill learning in rats
Adaneuda Silva BrittoSampaioaCaroline CristianoRealbcdRita Mara SoaresGutierrezaMonique PatricioSingulanideSandra ReginaAloucheaLuiz RobertoBrittodRaquel SimoniPiresa
doi : 10.1016/j.bbr.2021.113480
Volume 414, 24 September 2021, 113480
Learning complex motor skills is an essential process in our daily lives. Moreover, it is an important aspect for the development of therapeutic strategies that refer to rehabilitation processes since motor skills previously acquired can be transferred to similar tasks (motor skill transfer) or recovered without further practice after longer delays (motor skill retention). Different acrobatic exercise training (AE) protocols induce plastic changes in areas involved in motor control and improvement in motor performance. However, the plastic mechanisms involved in the retention of a complex motor skill, essential for motor learning, are not well described. Thus, our objective was to analyze the brain plasticity mechanisms involved in motor skill retention in AE . Motor behavior tests, and the expression of synaptophysin (SYP), synapsin-I (SYS), and early growth response protein 1 (Egr-1) in brain areas involved in motor learning were evaluated. Young male Wistar rats were randomly divided into 3 groups: sedentary (SED), AE, and AE with retention period (AER). AE was performed three times a week for 8 weeks, with 5 rounds in the circuit. After a fifteen-day retention interval, the AER animals was again exposed to the acrobatic circuit. Our results revealed motor performance improvement in the AE and AER groups. In the elevated beam test, the AER group presented a lower time and greater distance, suggesting retention period is important for optimizing motor learning consolidation. Moreover, AE promoted significant plastic changes in the expression of proteins in important areas involved in control and motor learning, some of which were maintained in the AER group. In summary, these data contribute to the understanding of neural mechanisms involved in motor learning in an animal model, and can be useful to the construction of therapeutics strategies that optimize motor learning in a rehabilitative context.
Influence of aging on chronic unpredictable mild stress-induced depression-like behavior in male C57BL/6J mice
ShengWanga1GuilanHuangb1JieYancChangxiLidJianwenFengcQiChencXiaomengZhengcHaobinLiaJiangchaoLieLijingWangaHuiminLif
doi : 10.1016/j.bbr.2021.113486
Volume 414, 24 September 2021, 113486
Depression is a common psychiatric disorder that can occur throughout an individual’s lifespan. Chronic unpredictable mild stress (CUMS) protocol is currently the most commonly used to develop an animal model of depression. Due to the variable duration and procedure of CUMS, it is difficult to reproduce and explore the mechanism of CUMS-induced depression effectively. In the present study, the CUMS-induced behavioral phenotypes were assessed in male C57BL/6J mice at the age of 9–18 weeks. The mice stressed for 3–8 weeks exhibited lower body weight as well as longer immobility time of forced swim and tail suspension test compared to control mice. Moreover, lessening and impairment of hippocampal neurons was found in stressed mice at the age of 18 weeks, which was correlated with increased relative mRNA expression levels of inflammatory cytokines BDNF, Htr1a, and IL-6 in the hippocampus. Nevertheless, no difference between stressed and control mice was observed neither in the sucrose preference nor in the open field test (except for vertical activity in OFT) at the age of 18 weeks. These findings reveal that 3–8 weeks of chronic stress could induce depression-like alterations in male C57BL/6J mice and the behavioral adaptation of aged mice might fail to the availability of the depression model.
Sex-specific behavioral and structural alterations caused by early-life stress in C57BL/6 and BTBR mice
Vasiliy V.ReshetnikovaKseniya A.AyriyantsaYulia A.RyabushkinaaNikita G.SozonovabNatalya P.Bondara
doi : 10.1016/j.bbr.2021.113489
Volume 414, 24 September 2021, 113489
Lately, the development of various mental illnesses, such as depression, personality disorders, and autism spectrum disorders, is often associated with traumatic events in childhood. Nonetheless, the mechanism giving rise to this predisposition is still unknown. Because the development of a disease often depends on a combination of a genetic background and environment, we decided to evaluate the effect of early-life stress on BTBR mice, which have behavioral, neuroanatomical, and physiological features of autism spectrum disorders. As early-life stress, we used prolonged separation of pups from their mothers in the first 2 weeks of life (3 h once a day). We assessed effects of the early-life stress on juvenile (postnatal day 23) and adolescent (postnatal days 37–38) male and female mice of strains C57BL/6 (B6) and BTBR. We found that in both strains, the early-life stress did not lead to changes in the level of social behavior, which is an important characteristic of autism-related behavior. Nonetheless, the early-life stress resulted in increased locomotor activity in juvenile BTBR mice. In adolescent mice, the stress early in life caused a low level of anxiety in B6 males and BTBR females and increased exploratory activity in adolescent BTBR males and females. In addition, adolescent B6 male and female mice with a history of the early-life stress tended to have a thinner motor cortex as assessed by magnetic resonance imaging. As compared to B6 mice, BTBR mice showed reduced levels of social behavior and exploratory activity but their level of locomotor activity was higher. BTBR mice had smaller whole-brain, cortical, and dorsal hippocampal volumes; decreased motor cortex thickness; and increased ventral-hippocampus volume as compared to B6 mice, and these parameters correlated with the level of exploratory behavior of BTBR mice. Overall, the effects of early postnatal stress are sex- and strain-dependent.
On the impairment of executive control of attention in chronic tinnitus: Evidence from the attention network test
MartinJensenab1EvaHüttenrauchaJochenMüller-MazzottacBoris A.StuckcCorneliaWeisea12
doi : 10.1016/j.bbr.2021.113493
Volume 414, 24 September 2021, 113493
Subjective, chronic tinnitus is a condition that is common in most populations. Whereas many individuals tend to habituate to tinnitus over time, for some their attention seems pathologically drawn towards the sensation. For this subgroup of individuals with severe tinnitus, dysfunctional executive attention has been suggested to be implicated in the failure to habituate. However, since most previous studies have used attention tests with low validity and specificity in this assessment, there is a need for further corroborating studies. In the present study, the Attention Network Test was used to compare mainly the efficiency of executive attention between a group of individuals with chronic tinnitus (TG; n = 33) and a healthy control group (CG; n = 37). The results showed that individuals with chronic tinnitus, compared to the CG, did not present with a specific impairment in executive control of attention, nor in any of the other two attention domains. These findings are discussed in relation to the sampling characteristics in this study, which might have led to the sample being more homogenous and high functioning than samples in tinnitus studies generally. Overall, this study suggests that tinnitus and executive control of attention impairment might not be directly related, and that the latter might not necessarily be associated with the maintenance of the condition.
Baicalin ameliorates chronic unpredictable mild stress-induced depression through the BDNF/ERK/CREB signaling pathway
ZhixiaJiaa1JialiYanga1ZhuoqingCaoa1JingZhaobJinhuZhangbYeLubLiChuaShaodanZhangcYuanChencLinPeib
doi : 10.1016/j.bbr.2021.113463
Volume 414, 24 September 2021, 113463
Brain-derived neurotrophic factor (BDNF) can activate the extracellular regulated protein kinase (ERK)/cAMP response element binding protein (CREB) cascade revealing an important role in antidepressant effects. Here, we studied the neuroprotective effect of baicalin (BA) in mice with chronic unpredictable mild stress (CUMS)-induced via a BDNF/ERK/CREB signaling pathway. Depression was induced via six weeks of CUMS in male ICR mice, and drug therapy was given simultaneously for the last three weeks. Cognitive dysfunctions were then evaluated via sucrose preference test (SPT), open field test (OFT), Morris water maze test (MWM), tail suspension test (TST), and novelty suppressed feeding test (NSF). Western blot and real-time PCR were then used to detect the relative expression of ERK, CREB, p-ERK, and p-CREB. Integrated optical density (IOD) tests of p-ERK and p-CREB were then evaluated via immunofluorescence. The behavior results showed that the cognitive dysfunctions increased in the CUMS group versus the control (CON) group (p < 0.01). There were decreases in fluoxetine (FLU) and BA groups (p < 0.05, p < 0.01). The protein ratios of p-ERK/ERK, p-CREB/CREB and ERK mRNA, and CREB mRNA expression decreased in the CUMS group (p < 0.01) and markedly increased in the FLU and BA groups (p < 0.05, p < 0.01). The IOD value of the p-ERK and p-CREB in the CUMS group was decreased versus the CON group (p < 0.01), and these changes were improved via BA and FLU treatment (p < 0.05, p < 0.01). This study indicated that BA can improve cognitive functions and has antidepressant effects in mice, which may be associated with activation of the BDNF/ERK/CREB signaling pathway in the hippocampus.
Role of hippocampal orexin receptors in antinociception elicited by chemical stimulation of the lateral hypothalamus in the tail-flick test
AfsanehZargaraniaSaeidehKarimi-HaghighibAbbasHaghparasta
doi : 10.1016/j.bbr.2021.113492
Volume 414, 24 September 2021, 113492
The lateral hypothalamus (LH) orexinergic neurons project to numerous brain regions implicated in pain perception, including the CA1 part of the hippocampal formation. Moreover, the roles of orexin receptors (OXRs) in the CA1 in anti-analgesic consequences of the LH chemical stimulation by carbachol, muscarinic receptor agonist, in acute pain have not been clarified. The current research showed OXRs antagonist administration's effect in the CA1 on analgesia elicited by the LH chemical stimulation in a tail-flick test as an acute model of pain. The control groups, including vehicle-control groups, were given intra-LH administration of saline (0.5 ?L), following intra-CA1 infusion of DMSO (12 %; 0.5 ?L), and carbachol-control groups were treated with carbachol (250 nM/0.5 ?L saline) into the LH following DMSO in the CA1. Treated groups received SB334867 (1, 3, 10, and 30 nM/0.5 ?L DMSO) or TCS OX2 29 (0.1, 1, 10, and 20 nM/0.5 ?L DMSO) as OX1R or OX2R antagonist, respectively, in the CA1 prior intra-LH administration of carbachol. After all injections, all rats underwent the tail-flick test over a 60-min time. Infusion of SB334867 or TCS OX2 29 in the CA1 impaired the analgesic consequences following chemical stimulation of the LH in acute pain. Meanwhile suppressive impact of the OX1R or OX2R antagonist on the analgesic impact of LH chemical stimulation was approximately identical. The current investigation provided a new document about the critical involvement of hippocampal orexinergic system in the modulatory role of the LH-CA1 path in pain perception.
Hyperactivation of the amygdala correlates with impaired social play behavior of prepubertal male rats in a maternal immune activation model
FernandoVitor-VieiraFabiana C.VilelaAlexandreGiusti-Paiva
doi : 10.1016/j.bbr.2021.113503
Volume 414, 24 September 2021, 113503
Maternal infection during pregnancy is an environmental risk factor for neurodevelopmental dysfunction, such as autism spectrum disorder (ASD). This study investigated the effect of maternal immune activation (MIA) on the behavior profile of prepubertal offspring and whether MIA alters the neuronal activation pattern of brain areas related to social play behavior. Pregnant Wistar rats received 500 ?g/kg of lipopolysaccharide or saline solution on gestational day 16. Their offspring were tested using behavioral tasks to capture some of the core and associated ASD-like symptoms. Neuronal activation, indexed via c-fos expression after social play behavior, was evaluated in several brain areas. MIA had a number of adverse effects on dams and reduced the number of successful births and litter size. MIA induced sex-specific autistic?like features by a reduction in ultrasonic vocalizations in response to separation from the mother and nest, reduction in discrimination between neutral odors and their nest odor, moderate effect in stereotypies in the hole-board test, impaired risk assessment phenotype, and reduction in social play behavior without changes in locomotor activity only in prepubertal male offspring. A decrease in social play behavior may be associated with a decrease in the number of c-fos-positive cells in the prefrontal cortex and striatum, but hyperactivation of the basolateral and basomedial amygdala. Prenatal immune challenge results in ASD-like symptoms such as impaired risk assessment behavior, communication, and social interactions in male prepubertal offspring. Impaired social play behavior is correlated with neuronal hyperactivation in the amygdala.
Maternal immune activation leads to atypical turning asymmetry and reduced DRD2 mRNA expression in a rat model of schizophrenia
AnnakarinaMundorfabNadjaKubitzaaKarolaHüntenaHiroshiMatsuicGeorgJuckelaSebastianOcklenburgdNadjaFreunda
doi : 10.1016/j.bbr.2021.113504
Volume 414, 24 September 2021, 113504
Atypical asymmetries have been reported in individuals diagnosed with schizophrenia, linking higher symptom severity to weaker lateralization. Furthermore, both lateralization and schizophrenia are influenced by the dopaminergic system. However, whether a direct link between the etiology of schizophrenia and atypical asymmetries exists is yet to be investigated. In this study, we examined whether maternal immune activation (MIA), a developmental animal model for schizophrenia and known to alter the dopaminergic system, induces atypical lateralization in adolescent and adult offspring. As the dopaminergic system is a key player in both, we analyzed neuronal dopamine D2 receptor (DRD2) mRNA expression. MIA was induced by injecting pregnant rats with 10 mg/kg polyinosinic:polycytidylic (PolyI:C) at gestational day 15. Controls were injected with 0.9 % NaCl. Offspring were tested at adolescence or early adulthood for asymmetry of turning behavior in the open field test. The total number of left and right turns per animal was assessed using DeepLabCut. Strength and preferred side of asymmetry were analyzed by calculating lateralization quotients. Additionally, DRD2 mRNA expression in the prefrontal cortex of offspring at both ages was analyzed using real-time PCR. MIA was associated with a rightward turning behavior in adolescents. In adults, MIA was associated with an absence of turning bias, indicating reduced asymmetry after MIA. The analysis of DRD2 mRNA expression revealed significantly lower mRNA levels after MIA compared to controls in adolescent, but not adult animals. Our results reinforce the association between atypical asymmetries, reduced DRD2 mRNA expression, and schizophrenia. However, more preclinical research is needed.
The processing characteristics of bodily expressions under the odor context: An ERP study
DanyangLiXiaochunWang
doi : 10.1016/j.bbr.2021.113494
Volume 414, 24 September 2021, 113494
The recognition of facial expressions has been shown to be influenced by contextual odors. The aims of this study were (1) to investigate whether odor has a similar effect on the recognition of bodily expressions, and (2) to analyze the time-course of such effects. Sixty-nine adults were randomized into three groups to identify bodily expressions (happy, fearful, and neutral) in three odor environments (pleasant odor, unpleasant odor, and no odor). Event-related potentials (ERPs) induced by the viewing bodily expressions were analyzed. Behaviorally, the unpleasant odor context promoted the recognition of bodily expressions. The ERP results showed odor influences on bodily expression recognition in two phases. In a middle stage phase (150–200?ms post-stimulus onset), VPP amplitudes induced by bodily expressions were greater in an unpleasant odor context than in a pleasant odor context. In a mid-late stage phase (beyond 200?ms), an interaction between contextual odor and bodily expression type was observed. When exposed to an unpleasant contextual odor, N2 and LPP amplitudes related to fearful bodily expressions were smaller than when exposed to other odor contexts, showing the promoting effect of mood coherence effect. Behavioral and ERP evidence confirmed that contextual odor can modulate the visual processing of bodily expressions, with an overall promoting effect of an unpleasant odor on bodily expression processing (phase one) and a specific modulating influence of odors on affectively congruent/incongruent bodily expressions (phase two).
Treadmill exercise overcomes memory deficits related to synaptic plasticity through modulating ionic glutamate receptors
BaixiaLiabQianMaoabNaZhaoabJieXiaabYongcaiZhaocBoXuab
doi : 10.1016/j.bbr.2021.113502
Volume 414, 24 September 2021, 113502
Neuronal death and synaptic loss are major pathogensis of Alzheimer’s disease (AD), which may be related to the ionic glutamate receptors abnormality. Ionic glutamate receptors are important postsynaptic membrane receptors that regulate excitatory synaptic transmission and are also major component of the postsynaptic density. Beta-Amyloid (A?) attacks ionic glutamate receptors to reduce synaptic efficacy and synaptic plasticity, resulting in neuronal death and synaptic loss. The current study aimed to investigate whether exercise-ameliorated AD was associated with changes in ionic glutamate receptors. Transgenic APP/PS1 mice (TgAPP/PS1) and age-matched littermate wild mice were divided into wild type control group, wild type exercise group, transgenic control group and transgenic exercise group. The mice in exercise groups were subjected to treadmill training for 12 weeks. The results showed that 12-week treadmill exercise improved the spatial learning and memory abilities of TgAPP/PS1 mice. Moreover, exercise decreased the contents of A?40, A?42 and amyloid plaque deposition in hippocampus of TgAPP/PS1 mice. The number of synapses and the length and thickness of postsynaptic densities (PSD) in the hippocampal CA1 region of TgAPP/PS1 mice were significantly increased after exercise. Concomitantly, TgAPP/PS1 displayed obstacles in synaptic plasticity as evidenced by significant decreases in the levels of synaptic structural plasticity-related proteins SYN, PSD95, MAP2 and NCAM, as well as ionic glutamate neuroreceptor subunit proteins GluN2B and GluA1. Interestingly, exercise alleviated these synaptic plasticity disorder in TgAPP/PS1 mice. Thus, this study demonstrates that 12-week treadmill exercise reduces A? levels in the hippocampus and mitigates cognitive decline in TgAPP/PS1 mice, which may be mediated by improvements in synaptic structural plasticity and excitatory neurotransmission.
Juvenile stress increases cocaine-induced impulsivity in female rats
Tracie A.PaineSarahBrainardEmmaKepplerRachelPoyleEliseSai-HardebeckVaughanSchwobCeceliaTannous-Taylor
doi : 10.1016/j.bbr.2021.113488
Volume 414, 24 September 2021, 113488
In humans, adverse childhood experiences are associated with an increased risk of developing a neuropsychiatric disorder. Changes in social behavior and cognitive function are hallmarks of numerous neuropsychiatric disorders. Here we examined the effects of exposure to variable stress during the juvenile period on social behavior, reward, and cognitive function (as measured in the 5-choice serial reaction time task (5CSRTT)) in rats. From postnatal days (PND) 25–29 male and female rats were exposed to a variable stress protocol. In adulthood, social interactions and sucrose preference were assessed prior to training on the 5CSRTT. Once successfully trained, rats were challenged with different task versions, and then the effects of cocaine (0, 10, or 20 mg/kg, IP) on performance were assessed. A follow-up experiment examined the ability of the D2 receptor antagonist eticlopride (0.0, 0.025, 0.05 mg/kg, IP) to block the effects of cocaine on 5CSRTT performance in female rats. Male rats exposed to juvenile stress tended to engage in less social behavior and had an increased correct response latency in the 5CSRTT following cocaine administration. Female rats exposed to juvenile stress exhibited a trend towards increased social behavior and demonstrated increased cocaine-induced impulsivity. The increase in impulsivity was not blocked by co-administration of eticlopride. Juvenile stress had minimal effects on adult behavior in male rats, but increased cocaine-induced impulsivity in female rats. Such an effect could contribute to the enhanced escalation of drug-use observed in females that experience juvenile stress. This possibility awaits further testing.
Reelin changes hippocampal learning in aging and Alzheimer’s disease
Austin T.MarckxabKatja E.FritschleabLaurentCalvierabJoachimHerzabcd
doi : 10.1016/j.bbr.2021.113482
Volume 414, 24 September 2021, 113482
The hippocampal formation (HF) is a neuroanatomical region essential for learning and memory. As one of the earliest regions to display the histopathological hallmarks of Alzheimer’s disease (AD), determining the specific mechanisms of the HF’s vulnerability is of capital importance. Reelin, a glycoprotein crucial in cortical lamination during embryonic neurogenesis, has an uncommon expression pattern within the HF and has been implicated in both learning and AD pathogenesis. We hypothesized that Reelin deficiency would expedite behavioral impairments which accompany normal aging. Additionally, we hypothesized that Reelin deficiency in the presence of mutated human microtubule associated protein tau (MAPT) would further impair hippocampal function. To test our hypothesis, we utilized cohorts of aged mice, aged mice with Reelin conditional knockout (RcKO), and adult mice with both RcKO and MAPT in the Barnes maze and Trace fear conditioning. Consistent with prior literature, increased age in wild-type mice was sufficient to reduce spatial searching in the Barnes maze. Increased age both exacerbated spatial impairments and altered context learning in RcKO mice. Lastly, adult mice with both RcKO and the MAPT transgene displayed both the lowest age-of-onset and most severe spatial learning deficits. In conclusion, Reelin deficiency when combined with AD risk-factors produced consistent impairments in spatial memory tasks. Furthermore, our results further implicate Reelin’s importance in both HF homeostasis and AD pathogenesis.
Extended operant training increases infralimbic and prelimbic cortex Fos regardless of fear conditioning experience
AlisaPajserChristianFosterBrookeGaeddertCharles L.Pickens
doi : 10.1016/j.bbr.2021.113476
Volume 414, 24 September 2021, 113476
Extended fear training can lead to initially low fear expression that grows over time, termed fear incubation. Conversely, a single fear conditioning session typically results in high fear initially that is sustained over time. Fear expression decreases across extended training, suggesting that a fear extinction-like process might be responsible for low fear observed soon after training. Because of the prominent role medial prefrontal cortex (mPFC) plays in fear conditioning and extinction, we decided to examine Fos expression resulting from a cued fear retrieval test to gain insight into possible mechanisms involved in extended training fear incubation. Male Long-Evans rats received 1 or 10 days of tone-shock pairings or tone-only exposure (while lever-pressing for food). Two days after the end of fear training, rats received a cued fear test, with perfusions timed to visualize Fos expression during test. As expected, the limited fear conditioning group exhibited higher fear in the test than any of the other groups (as measured with conditioned suppression of lever-pressing). Interestingly, we found that extended training animals (whether they received tone-shock pairings or tone-only exposure) expressed higher levels of Fos in both prelimbic and infralimbic cortices than limited training animals. There was no association between fear expression and mPFC Fos expression. These results suggest we may have visualized Fos expression related to operant overtraining rather than conditioned fear related processes. Further research is needed to determine the neurobiological basis of extended training fear incubation and to determine processes represented by the pattern of Fos expression we observed.
Polymorphisms in the FKBP5 gene are associated with attention deficit and hyperactivity disorder in Korean children
Hyung JunKimHan JunJin
doi : 10.1016/j.bbr.2021.113508
Volume 414, 24 September 2021, 113508
Attention deficit hyperactivity disorder (ADHD) is a common and heritable childhood psychiatric disorder. Recently, many studies reported a down-regulated hypothalamus–pituitary–adrenal axis (HPA-axis) with low cortisol levels in children with ADHD. The FK506 binding protein 5 or FKBP5 gene regulates the negative feedback of the HPA-axis, and genetic variants in this gene showed an association with ADHD. We investigated the genetic association between FKBP5 gene polymorphisms and susceptibility to ADHD in Korean children. We conducted a case-control study with 150 ADHD children and 322 controls. Genotyping of FKBP5 rs9394309 and rs7748266 was performed by using polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP). Our results showed that rs7748266 polymorphism has significant genotype (p = 0.021) and allele (p = 0.009) frequency differences between children with ADHD and the control group. CT genotype [odds ratio (OR) 1.70, 95 % confidence interval (CI) 1.134–2.540, p = 0.010] and T allele (OR 1.54, 95 % CI 1.114–2.117, p = 0.009) were associated with increased risk of ADHD. In addition, dominant (p = 0.006) and over-dominant genetic (p = 0.016) models showed significant associations with ADHD. In the stratified analysis, a significant result was obtained from the girl samples (p = 0.048). The OR of the girls with ADHD with CT genotype was 2.29 (95 % CI 1.170–4.469, p = 0.014). In contrast to rs7748266 polymorphism, rs9394309 polymorphism did not show any significant result (p > 0.05). Haplotype analysis also revealed a significant difference of the Tsingle bondG haplotype for rs7748266 – rs9394309 (p = 0.028, global haplotype association p-value of 0.0091). Conclusively, we confirmed that FKBP5 gene polymorphisms were associated with ADHD in Korean children. These results suggested that FKBP5 may factor in the development of ADHD.
Quantification of brainstem norepinephrine relative to vocal impairment and anxiety in the Pink1-/- rat model of Parkinson disease
Jesse D.HoffmeisterabCynthia A.Kelm-NelsonbMichelle R.Ciucciabc
doi : 10.1016/j.bbr.2021.113514
Volume 414, 24 September 2021, 113514
Vocal communication impairment and anxiety are co-occurring and interacting signs of Parkinson Disease (PD) that are common, poorly understood, and under-treated. Both vocal communication and anxiety are influenced by the noradrenergic system. In light of this shared neural substrate and considering that noradrenergic dysfunction is a defining characteristic of PD, tandem investigation of vocal impairment and anxiety in PD relative to noradrenergic mechanisms is likely to yield insights into the underlying disease-specific causes of these impairments. In order to address this gap in knowledge, we assessed vocal impairment and anxiety behavior relative to brainstem noradrenergic markers in a genetic rat model of early-onset PD (Pink1-/-) and wild type controls (WT). We hypothesized that 1) brainstem noradrenergic markers would be disrupted in Pink1-/-, and 2) brainstem noradrenergic markers would be associated with vocal acoustic changes and anxiety level. Rats underwent testing of ultrasonic vocalization and anxiety (elevated plus maze) at 4, 8, and 12 months of age. At 12 months, brainstem norepinephrine markers were quantified with immunohistochemistry. Results demonstrated that vocal impairment and anxiety were increased in Pink1-/- rats, and increased anxiety was associated with greater vocal deficit in this model of PD. Further, brainstem noradrenergic markers including TH and ?1 adrenoreceptor immunoreactivity in the locus coeruleus, and ?1 adrenoreceptor immunoreactivity in vagal nuclei differed by genotype, and were associated with vocalization and anxiety behavior. These findings demonstrate statistically significant relationships among vocal impairment, anxiety, and brainstem norepinephrine in the Pink1-/- rat model of PD.
Skilled reach training enhances robotic gait training to restore overground locomotion following spinal cord injury in rats
Nathan D.NeckelabHainingDaiaJohnHanckelaYichienLeecdChristopherAlbanesecdOlgaRodriguezcd
doi : 10.1016/j.bbr.2021.113490
Volume 414, 24 September 2021, 113490
Rehabilitative training has been shown to improve motor function following spinal cord injury (SCI). Unfortunately, these gains are primarily task specific; where reach training only improves reaching, step training only improves stepping and stand training only improves standing. More troublesome is the tendency that the improvement in a trained task often comes at the expense of an untrained task. However, the task specificity of training does not preclude the benefits of combined rehabilitative training. Here we show that robot assisted gait training alone can partially reduce the deficits in unassisted overground locomotion following a C4/5 overhemisection injury in rats. When robot-assisted gait training is done in conjunction with skilled forelimb training, we observe a much greater level of recovery of unassisted overground locomotion. In order to provide reach training that would not interfere with our robotic gait training schedule, we prompted rats to increase the use of their forelimbs by replacing the standard overhead feeder with a custom made, deep welled hopper that dispensed nutritionally equivalent small milled pellets. We speculate that the increase in recovery from combined training is due to a more robust interneuronal relay network around the injury site. in vivo manganese-enhanced magnetic resonance imaging of the spinal cord indicated that there was no increase in the cellular activity, however ex vivo diffusion tensor imaging (DTI) suggested an increase in collateralization around the injury site in rats that received both reach training and robot assisted gait training.
Specific stimulation of PV+ neurons at early stage ameliorates prefrontal ischemia-induced spatial working memory impairment
LinChena1JunHub1JiankunMuc1ChaoLidGuang-yanWueChaoHefYouhongXiecJian-ningYeg
doi : 10.1016/j.bbr.2021.113511
Volume 414, 24 September 2021, 113511
Prefrontal ischemia can cause impairments in learning and memory, executive functions and cognitive flexibility. However, the related cellular mechanisms at the early stage are still elusive. The present study used ischemic stroke in medial prefrontal cortex and systemically investigated the electrophysiological changes of the parvalbumin (PV+) interneurons 12?h post ischemia. We found that Ih and the related voltage sags in PV+ interneurons are downregulated post ischemia, which correlates with hyperpolarization of the membrane potentials and increased input resistance in these interneurons. Consistent with the suppression of Ih, postischemic PV+ interneurons exhibited a reduction in excitability and exerted a less inhibitory control over the neighboring pyramidal excitatory neurons. Moreover, we found that specifically chemogenetic activation of PV+ neurons at early stage ameliorated prefrontal ischemia-induced spatial working memory dysfunction in T-maze without effects on the locomotor coordination and balance. In contrast, suppression of PV+ neurons by blockade of Ih leaded to further aggravate the damage of spatial memory. These findings indicate that dysfunctional Ih in the PV+ neuron postischemia induces the imbalance of excitation and inhibition, which might represent a novel mechanism underlying the prefrontal ischemia-induced cognitive impairment.
Prominent health problems, socioeconomic deprivation, and higher brain age in lonely and isolated individuals: A population-based study
Ann-Marie G.de LangeabcTobiasKaufmannbdDaniel S.QuintanabefAdrianoWintertonbOle A.AndreassenbfLars T.WestlyebefKlaus P.Ebmeiera
doi : 10.1016/j.bbr.2021.113510
Volume 414, 24 September 2021, 113510
Loneliness is linked to increased risk for Alzheimer's disease, but little is known about factors potentially contributing to adverse brain health in lonely individuals. In this study, we used data from 24,867 UK Biobank participants to investigate risk factors related to loneliness and estimated brain age based on neuroimaging data. The results showed that on average, individuals who self-reported loneliness on a single yes/no item scored higher on neuroticism, depression, social isolation, and socioeconomic deprivation, performed less physical activity, and had higher BMI compared to individuals who did not report loneliness. In line with studies pointing to a genetic overlap of loneliness with neuroticism and depression, permutation feature importance ranked these factors as the most important for classifying lonely vs. not lonely individuals (ROC AUC?=?0.83). While strongly linked to loneliness, neuroticism and depression were not associated with brain age estimates. Conversely, objective social isolation showed a main effect on brain age, and individuals reporting both loneliness and social isolation showed higher brain age relative to controls – as part of a prominent risk profile with elevated scores on socioeconomic deprivation and unhealthy lifestyle behaviours, in addition to neuroticism and depression. While longitudinal studies are required to determine causality, this finding may indicate that the combination of social isolation and a genetic predisposition for loneliness involves a risk for adverse brain health. Importantly, the results underline the complexity in associations between loneliness and adverse health outcomes, where observed risks likely depend on a combination of interlinked variables including genetic as well as social, behavioural, physical, and socioeconomic factors.
Noradrenergic alpha-2A receptor activation suppresses courtship vocalization in male Japanese quail
YasukoTobariabAmiMasuzawaaNorikaHaradaaKentaSuzukicSimone L.Meddled
doi : 10.1016/j.bbr.2021.113513
Volume 414, 24 September 2021, 113513
Male Japanese quail produce high-frequency crow vocalizations to attract females during the breeding season. The nucleus of intercollicularis (ICo) is the midbrain vocal center in birds and electrical stimulation of the ICo produces calls that include crowing. Noradrenaline plays a significant role in sexual behavior but the contribution of noradrenaline in the control of courtship vocalizations in quail has not been well established. Using dose-dependent intracerebroventricular injection of clonidine, an ?2-adrenergic receptor-specific agonist, crowing vocalization was immediately suppressed. At the same time as crow suppression by clonidine there was a reduction of immediate early gene, zenk mRNA, in the ICo; no zenk mRNA expression was detected in the dorsomedial division of the nucleus. Using histochemistry, we determined that the ICo receives noradrenergic innervation and expresses ?2A-adrenergic receptor mRNA. Taken together, these data suggest that noradrenaline regulates courtship vocalization in quail, possibly via the ?2A-adrenergic receptor expressed on ICo neurons.
Behavioral and neurochemical effects of folic acid in a mouse model of depression induced by TNF-?
JosianeBudni1MorganaMorettiAndiara E.FreitasVivian B.NeisCamille M.RibeiroGrasielade Oliveira BalenDébora K.RiegerRodrigo B.LealAna L?cia S.Rodrigues
doi : 10.1016/j.bbr.2021.113512
Volume 414, 24 September 2021, 113512
Folic acid has been reported to exert antidepressant effects, but its ability to abrogate the depressive-like behavior and signaling pathways alterations elicited by an inflammatory model of depression remains to be established. This study examined: a) the efficacy of folic acid in a mouse model of depression induced by tumor necrosis factor (TNF-?); b) whether the administration of subthreshold doses of folic acid and antidepressants (fluoxetine, imipramine, and bupropion), MK-801, or 7-nitroindazole cause antidepressant-like effects; c) the effects of TNF-? and/or folic acid on hippocampal p38MAPK, Akt, ERK, and JNK phosphorylation. Folic acid reduced the immobility time in the tail suspension test (TST) in control mice (10–50 mg/kg, p.o) and abolished the depressive-like behavior elicited by TNF-? (0.001 fg/site, i.c.v.) in this test (1–50 mg/kg, p.o). Coadministration of subthreshold doses of folic acid (1 mg/kg, p.o.) and fluoxetine, imipramine, bupropion, MK-801, or 7-nitroindazole produced an antidepressant-like effect in mice exposed or not to TNF-?. TNF-?-treated mice presented increased p38MAPK phosphorylation and decreased Akt phosphorylation, and the later effect was prevented by folic acid (10 mg/kg, p.o.). Additionally, ERK1 phosphorylation was increased in mice treated with TNF-? + folic acid (1 mg/kg), but no effects on ERK2 or JNK1/2/3 phosphorylation were found in any group. The results indicate the efficacy of folic acid to counteract the depressive-like behavior induced by a pro-inflammatory cytokine, an effect that might be associated with the activation of monoaminergic systems, inhibition of N-methyl-d-aspartate (NMDA) receptors and nitric oxide (NO) synthesis, as well as Akt modulation.
Sex differences in behavioral traits related with high sensitivity to the reinforcing effects of cocaine
SergioPujante-GilCarmenManzanedoM. CarmenArenas
doi : 10.1016/j.bbr.2021.113505
Volume 414, 24 September 2021, 113505
Cocaine is the most prevalent illegal stimulant drug in Europe among the adult population. Its abuse is characterized by a faster substance abuse disorder (SUD) development than other drugs, with high vulnerability to relapse. However, there does not exist an effective treatment for cocaine dependence. Sex differences have been reported in psychological disorders including SUD. For this reason, it is essential to identify risk factors that predict susceptibility or resilience to cocaine addiction for the development of effective prevention strategies considering sex differences. In the present study, the main objective was to determine more sensitive phenotypes to the conditioned reinforcing effects of cocaine in both sexes. Anxiety-like behavior and the locomotor response to novelty were evaluated in the elevated plus maze, and despair in the tail suspension test, as well as vulnerability traits linked with a high sensitivity to the reinforcing effects of a subthreshold dose of cocaine (1 mg/kg) in the conditioned place preference (CPP) paradigm in male and female mice. Our results indicated that only female mice with high anxiety, low locomotor response to novelty or low despair levels acquired CPP induced by cocaine, while male mice with low anxiety, high locomotor response to novelty or high despair levels presented a higher susceptibility to the rewarding effects of cocaine than others. These sex differences in the results reveal an opposite pattern in males and females on the relationship between anxiety- and depressive-like behaviors and cocaine vulnerability, demonstrating the need to include female mice in preclinical studies.
Schizophrenia: Antipsychotics and drug development
GaryRemingtonabMargaret K.HahnabSri MahavirAgarwalabArabaChintohabOferAgidab
doi : 10.1016/j.bbr.2021.113507
Volume 414, 24 September 2021, 113507
The introduction of chlorpromazine and the work that ensued provided the foundation to reposition schizophrenia as a biological illness. The present paper follows the evolution of antipsychotics and their shift from ‘typical’ to ‘atypical’. Atypicality is reviewed in reference to its original definition, clozapine’s role, and developments that now leave the concept’s utility in question. In a similar fashion, drug development is reviewed in the context of the illness’ multiple symptom domains, as well as differences captured by clinical staging and phenotyping. Collectively, the evidence argues for a more nuanced approach to drug development that aligns with the illness’ heterogeneity and complexity. Just as ‘atypical’ as a descriptor for antipsychotics may be outdated, it may be time to set aside the notion of developing drugs that treat ‘schizophrenia’.
Mechanisms of higher-order learning in the amygdala
DilaraGostolupceMihaela D.IordanovaBelinda P.P.Lay
doi : 10.1016/j.bbr.2021.113435
Volume 414, 24 September 2021, 113435
Adaptive behaviour is under the potent control of environmental cues. Such cues can acquire value by virtue of their associations with outcomes of motivational significance, be they appetitive or aversive. There are at least two ways through which an environmental cue can acquire value, through first-order and higher-order conditioning. In first-order conditioning, a neutral cue is directly paired with an outcome of motivational significance. In higher-order conditioning, a cue is indirectly associated with motivational events via a directly conditioned first-order stimulus. The present article reviews some of the associations that support learning in first- and higher-order conditioning, as well as the role of the BLA and the molecular mechanisms involved in these two types of learning.
Stress gets into the belly: Early life stress and the gut microbiome
LiisaHantsooaBabette S.Zemelb
doi : 10.1016/j.bbr.2021.113474
Volume 414, 24 September 2021, 113474
Research has established that stress “gets under the skin,” impacting neuroendocrine and neuroimmune pathways to influence risk for physical and mental health outcomes. These effects can be particularly significant for early life stress (ELS), or adverse childhood experiences (ACEs). In this review, we explore whether stress gets “into the belly,” that is, whether psychosocial stress affects the gut microbiome. We review animal and human research utilizing a variety of stress paradigms (acute laboratory stressors, chronic stress, stressful life events, perceived stress, ELS, in utero stress) and their impacts on the gut microbiota, with a particular focus on ELS. We also review data on dietary interventions to moderate impact of stress on the gut microbiome. Our review suggests strong evidence that acute laboratory stress, chronic stress, and ELS affect the gut microbiota in rodents, and growing evidence that perceived stress and ELS may impact the gut microbiota in humans. Emerging data also suggests, particularly in rodents, that dietary interventions such as omega-3 fatty acids and pre- and pro-biotics may buffer against the effects of stress on the gut microbiome, but more research is needed. In sum, growing evidence suggests that stress impacts not only the neuroendocrine and neuroimmune axes, but also the microbiota-gut-brain-axis, providing a pathway by which stress may get “into the belly” to influence health risk.
Prenatal stress-induced disruptions in microbial and host tryptophan metabolism and transport
Jeffrey D.GalleyabHelen J.ChenabcAdrienne M.AntonsonabTamar L.Gurabcd
doi : 10.1016/j.bbr.2021.113471
Volume 414, 24 September 2021, 113471
The aromatic amino acid tryptophan (Trp) is a precursor for multiple metabolites that can steer proper immune and neurodevelopment as well as social behavior in later life. Dysregulation in the Trp metabolic pathways and abundance of Trp or its derivatives, including indoles, kynurenine (Kyn), and particularly serotonin, has been associated with behavioral deficits and neuropsychiatric disorders including autism spectrum disorders (ASD) and schizophrenia. Previously, we have shown that prenatal stress (PNS) alters placental Trp and serotonin, and reduces Trp-metabolizing members of the maternal colonic microbiota. Given that PNS also results in alterations in offspring neurodevelopment, behavior and immune function, we hypothesized that PNS affects Trp metabolism and transport in both the maternal and fetal compartments, and that these alterations continue into adolescence. We surmised that this is due to reductions in Trp-metabolizing microbes that would otherwise reduce the Trp pool under normal metabolic conditions. To test this, pregnant mice were exposed to a restraint stressor and gene expression of enzymes involved in Trp and serotonin metabolism were measured. Specifically, tryptophan 2,3-dioxygenase, aryl hydrocarbon receptor, and solute carrier proteins, were altered due to PNS both prenatally and postnatally. Additionally, Parasutterella and Bifidobacterium, which metabolize Trp in the gut, were reduced in both the dam and the offspring. Together, the reductions of Trp-associated microbes and concomitant dysregulation in Trp metabolic machinery in dam and offspring suggest that PNS-induced Trp metabolic dysfunction may mediate aberrant fetal neurodevelopment.
