Neural basis of reward expectancy inducing proactive aggression.

Proactive aggression refers to deliberate and unprovoked behavior, typically motivated by personal gain or expected reward. Reward expectancy is generally recognized as a critical factor that may influence proactive aggression, but its neural mechanisms remain unknown. We conducted a task-based functional magnetic resonance imaging (fMRI) experiment to investigate the relationship between reward expectancy and proactive aggression. 37 participants (20 females, mean age = 20.8 ± 1.42, age range = 18-23 years) completed a reward-harm task. In the experiment, reward valence expectancy and reward possibility expectancy were manipulated respectively by varying amounts (low: 0.5-1.5 yuan; high: 10.5-11.5 yuan) and possibilities (low: 10%-30%; high: 70%-90%) of money that participants could obtain by choosing to aggress. Participants received fMRI scans throughout the experiment. Brain activation regions associated with reward expectancy mainly involve the middle frontal gyrus, lingual gyrus, inferior temporal gyrus, anterior cuneus, caudate nucleus, inferior frontal gyrus, cingulate gyrus, anterior central gyrus, and posterior central gyrus. Associations between brain activation and reward expectancy in the left insula, left middle frontal gyrus, left thalamus, and right middle frontal gyrus were found to be related to proactive aggression. Furthermore, the brain activation regions primarily involved in proactive aggression induced by reward expectancy were the insula, inferior frontal gyrus, inferior temporal gyrus, pallidum, and caudate nucleus. Under conditions of high reward expectancy, participants engage in more proactive aggressive behavior. Reward expectancy involves the activation of reward- and social-cognition-related brain regions, and these associations are instrumental in proactive aggressive decisions.

Neural correlates of aggression outcome expectation and their association with aggression: A voxel-based morphometry study.

BACKGROUND: Aggression outcome expectation is an important cognitive factor of aggression. Discovering the neural mechanism of aggression outcome expectation is conducive to developing aggression research. However, the neural correlates underlying aggression outcome expectation and its effect remain elusive. METHODS: We utilized voxel-based morphometry (VBM) to unravel the neural architecture of aggression outcome expectation measured by the Social Emotional Information Processing Assessment for Adults and its relationship with aggression measured by the Buss Perry Aggression Questionnaire in a sample of 185 university students (114 female; mean age = 19.94 ± 1.62 years; age range: 17-32 years). RESULTS: We found a significantly positive correlation between aggression outcome expectation and the regional gray matter volume (GMV) in the right middle temporal gyrus (MTG) (x = 55.5, y = -58.5, z = 1.5; t = 3.35; cluster sizes = 352, p < 0.05, GRF corrected). Moreover, aggression outcome expectation acted as a mediator underlying the association between the right MTG volume and aggression. CONCLUSIONS: These results revealed the neural correlates of aggression outcome expectation and its effect on aggression for the first time, which may contribute to our understanding of the cognitive neural mechanism of aggression and potentially identifying neurobiological markers for aggression.

Nano-Calcium Carbonate Affect the Respiratory and Function Through Inducing Oxidative Stress: A Cross-sectional Study Among Occupational Exposure of Workers and a Further Research for Underlying Mechanisms.

OBJECTIVE: The aim of the study is to investigate whether nano-calcium carbonate (nano-CaCO 3 ) occupational exposure could induce adverse health effects in workers. METHODS: A cross-sectional study was conducted in a nano-CaCO 3 manufacturing plant in China. Then, we have studied the dynamic distribution of nano-CaCO 3 in nude mice and examined the oxidative damage biomarkers of subchronic administrated nano-CaCO 3 on Sprague-Dawley rats. RESULTS: The forced vital capacity (%) and the ratio of FEV1 to FVC is the rate of one second of workers were significantly decreased than unexposed individuals. Dynamic imaging in mice of fluorescence labeled nano-CaCO 3 showed relatively high uptake and slow washout in lung. Similar to population data, the decline in serum glutathione level and elevation in serum MDA were observed in nano-CaCO 3 -infected Sprague-Dawley rats. CONCLUSIONS: We found that nano-CaCO 3 exposure may result in the poor pulmonary function in workers and lead to the changes of oxidative stress indexes.

Accelerated age-related decline in hippocampal neurogenesis in mice with noise-induced hearing loss is associated with hippocampal microglial degeneration.

Large-scale epidemiological surveys suggest that hearing loss (HL) is a significant risk factor for dementia. We previously showed that noise-induced HL (NIHL) impairs hippocampal cognitive function and decreases hippocampal neurogenesis and neuronal complexity, suggesting a causal role of HL in dementia. To further investigate the influence of acquired peripheral HL on hippocampal neurogenesis with the aging process as well as the underlying mechanism, we produced NIHL in male CBA/J mice and assessed hippocampal neurogenesis and microglial morphology in the auditory brain and hippocampus at 4 days post-noise exposure (DPN) or 1, 3, 6, or 12 months post-noise exposure (MPN) by immunofluorescence labeling. We found that the age-related decline in hippocampal neurogenesis was accelerated in mice with NIHL. Furthermore, in mice with NIHL, prolonged microglial activation occurred from 1 MPN to 12 MPN across multiple auditory nuclei, while aggravated microglial deterioration occurred in the hippocampus and correlated with the age-related decline in hippocampal neurogenesis. These results suggest that acquired peripheral HL accelerates the age-related decline in hippocampal neurogenesis and that hippocampal microglial degeneration may contribute to the development of neurodegeneration following acquired peripheral HL.

Age-related hearing loss in the Fischer 344/NHsd rat substrain.

Studies of the F344 rat have shown a variety of age-related auditory anatomy and physiology changes. The current study was undertaken to clarify the ARHL in the F344 rat, by examining the auditory pathway of the F344/NHsd substrain that is distributed by Harlan Laboratories for research in the United States. The F344/NHsd rat begins to lose its hearing at about 12 months, and by 24 months, there are 50-60 dB auditory brainstem response threshold shifts at 20 and 40 kHz and 20 dB losses at 5-10 kHz. Distortion product otoacoustic emissions (DPOAE) amplitudes at 1.8-12 kHz stimuli were depressed in the older (18-24 months) rats. Amplitude input-output functions of the compound action potential (CAP) were also depressed across frequency. The endocochlear potential (EP) was 90-100 mV in the 3 month old rats. All but one of the 24 month old rats' EPs were in the +75-85 mV range. Tympanometry revealed no differences in middle ear function between the young and older rats. Collectively, these findings suggest damage to the outer hair cells, but anatomical examination of the outer hair cells revealed a relative lack of cell loss compared to the magnitude of the hearing and DPOAE loss.

Prolonged low-level noise-induced plasticity in the peripheral and central auditory system of rats.

Prolonged low-level noise exposure alters loudness perception in humans, presumably by decreasing the gain of the central auditory system. Here we test the central gain hypothesis by measuring the acute and chronic physiologic changes at the level of the cochlea and inferior colliculus (IC) after a 75-dB SPL, 10-20-kHz noise exposure for 5weeks. The compound action potential (CAP) and summating potential (SP) were used to assess the functional status of the cochlea and 16 channel electrodes were used to measure the local field potentials (LFP) and multi-unit spike discharge rates (SDR) from the IC immediately after and one-week post-exposure. Measurements obtained immediately post-exposure demonstrated a significant reduction in supra-threshold CAP amplitudes. In contrast to the periphery, sound-evoked activity in the IC was enhanced in a frequency-dependent manner consistent with models of enhanced central gain. Surprisingly, one-week post-exposure supra-threshold responses from the cochlea had not only recovered, but were significantly larger than normal, and thresholds were significantly better than controls. Moreover, sound-evoked hyperactivity in the IC was sustained within the noise exposure frequency band but suppressed at higher frequencies. When response amplitudes representing the neural output of the cochlea and IC activity at one-week post exposure were compared with control animal responses, a central attenuation phenomenon becomes evident, which may play a key role in understanding why low-level noise can sometimes ameliorate tinnitus and hyperacusis percepts.

Prevention of noise-induced hearing loss with Src-PTK inhibitors.

Studies from our lab show that noise exposure initiates cell death by multiple pathways [Nicotera, T.M., Hu, B.H., Henderson, D., 2003. The caspase pathway in noise-induced apoptosis of the chinchilla cochlea. J. Assoc. Res. Otolaryngol. 4, 466-477] therefore, protection against noise may be most effective with a multifaceted approach. The Src protein tyrosine kinase (PTK) signaling cascade may be involved in both metabolic and mechanically induced initiation of apoptosis in sensory cells of the cochlea. The current study compares three Src-PTK inhibitors, KX1-004, KX1-005 and KX1-174 as potential protective drugs for NIHL. Chinchillas were used as subjects. A 30 microl drop of one of the Src inhibitors was placed on the round window membrane of the anesthetized chinchilla; the vehicle (DMSO and buffered saline) alone was placed on the other ear. After the drug application, the middle ear was sutured and the subjects were exposed to noise. Hearing was measured before and several times after the noise exposure and treatment using evoked responses. At 20 days post-exposure, the animals were anesthetized their cochleae extracted and cochleograms were constructed. All three Src inhibitors provided protection from a 4 h, 4 kHz octave band noise at 106 dB. The most effective drug, KX1-004 was further evaluated by repeating the exposure with different doses, as well as, substituting an impulse noise exposure. For all conditions, the results suggest a role for Src-PTK activation in noise-induced hearing loss (NIHL), and that therapeutic intervention with a Src-PTK inhibitor may offer a novel approach in the treatment of NIHL.

Cell junction proteins within the cochlea: A review of recent research.

Cell-cell junctions in the cochlea are highly complex and well organized. The role of these junctions is to maintain structural and functional integrity of the cochlea. In this review, we describe classification of cell junction-associated proteins identified within the cochlea and provide a brief overview of the function of these proteins in adherent junctions, gap junctions and tight junctions.

Evidence of a Common Pathway in Noise-Induced Hearing Loss and Carboplatin Ototoxicity.

In spite of the differences in the nature of the insult, the hearing loss from ototoxic drugs and noise exposure share a number of similarities in cochlear pathology. This paper explores the common factors between noise-induced hearing loss and ototoxicity by experimentally manipulating cochlear glutathione (GSH). In the first experiment, chinchillas were treated with a drop of saline (50 &mgr;l) on the round window of one ear and a drop of buthionine sulfoximine (BSO, 50 &mgr;l of 200 mM) on the other ear. BSO is a drug that blocks GSH synthesis and it was hypothesised that GSH-depressed ears would be more vulnerable to noise. Six hours after treatment, the animals were exposed to a 105 dB 4 kHz octave band noise for 4 hours, then a second dose of BSO was applied 2 hours later. The BSO treated ears showed more temporary threshold shifts and reduced GSH staining at day 4 post exposure, but there was no BSO effect in terms of greater permanent threshold shift (PTS) or hair cell loss. In the second experiment, chinchillas were pretreated with BSO and 3 days later were given either a single dose of carboplatin (25 mg/kg i.p.), a double dose (day 3 and 7) or only BSO. Chinchillas that received BSO and the double dose of carboplatin had significantly greater loss of inner and outer hair cells than the carboplatin chinchillas. In addition, the BSO and carboplatin chinchillas also had larger decreases in evoked response amplitudes suggesting that GSH depletion potentiated the ototoxicity of carboplatin. These results are discussed in terms of the role of reactive oxygen species in creating hearing loss and the potential protective role of glutathione.

[L-NAC protect hair cells in the rat cochlea from injury of exposure to styrene].

OBJECTIVE: To observe the effects of N-acetyl-L-cysteine (L-NAC) protect hair cells in the rat cochlea from injury of exposure to styrene. METHOD: Seventeen adult Long Evans rats were used in present study. The animals were randomly assigned into test group (n=9) and control group (n=8). The animals were exposed to styrene by gavage at 400 mg/kg (2 g styrene was mixed with 1 ml olive oil). Test group animals received styrene exposure plus L-NAC 325 mg/kg (L-NAC was dissolved in physiological saline solution) by intraperitoneal injection. Treatment was performed once a day, 5 days per week for 3 weeks. Control group animals received the same volume of saline injection on an identical time schedule used for the test group. The auditory brainstem response (ABR) thresholds of both ears elicited with clicks were measured before and at the end of the 3-week styrene or styrene plus L-NAC treatment. After hearing was re-assessed, animals were sacrificed and cochleae were quickly removed from the skull. Following fixation, whole specimens comprising the basilar membrane with Corti's organ were separated from the modiolus. The organs of Corti were stained with propidium iodide (PI) and the TUNEL assay to visualize the morphologic viability of hair cell nuclei, FITC-labeled phalloidin, a F-actin intercalating fluorescent probe used to visualize the morphologic viability of cuticular plate and the stereocilia in the hair cells. Each organ of Corti was thoroughly examined using fluorescence microscopy. The numbers of damaged OHCs (apoptotic, necrotic and missing OHCs) were documented. RESULT: There was a statistically significant decrease in ABR threshold shift (P<0.05) in the styrene-plus-L-NAC treated animals. The average percentage of damaged OHCs in the styrene-treated animals was 28.3%. In contrast, the average percentage of OHC damage in the styrene-plus-L-NAC treated group was only 10.6% (P<0.01). The percentage of reduction in the number of apoptotic cells in styrene-plus-L-NAC treated group was 78% (P<0.01). However, the mean reduction of necrotic cells was only 23% (P>0.05). CONCLUSION: The results indicate that the treatment with L-NAC may effectively protect against the styrene-induced hair cells damage and preferably reduce the number of apoptotic OHCs.

Noise induced changes in the expression of p38/MAPK signaling proteins in the sensory epithelium of the inner ear.

Noise exposure is a major cause of hearing loss. Classical methods of studying protein involvement have provided a basis for understanding signaling pathways that mediate hearing loss and damage repair but do not lend themselves to studying large networks of proteins that are likely to increase or decrease during noise trauma. To address this issue, antibody microarrays were used to quantify the very early changes in protein expression in three distinct regions of the chinchilla cochlea 2h after exposure to a 0.5-8 kHz band of noise for 2h at 112 dB SPL. The noise exposure caused significant functional impairment 2h post-exposure which only partially recovered. Distortion product otoacoustic emissions were abolished 2h after the exposure, but at 4 weeks post-exposure, otoacoustic emissions were present, but still greatly depressed. Cochleograms obtained 4 weeks post-exposure demonstrated significant loss of outer hair cells in the basal 60% of the cochlea corresponding to frequencies in the noise spectrum. A comparative analysis of the very early (2h post-exposure) noise-induced proteomic changes indicated that the sensory epithelium, lateral wall and modiolus differ in their biological response to noise. Bioinformatic analysis of the cochlear protein profile using "The Database for Annotation, Visualization and Integrated Discovery 2008" (DAVID - http://david.abcc. ncifcrf.gov) revealed the initiation of the cell death process in sensory epithelium and modiolus. An increase in Fas and phosphorylation of FAK and p38/MAPK in the sensory epithelium suggest that noise-induced stress signals at the cell membrane are transmitted to the nucleus by Fas and focal adhesion signaling through the p38/MAPK signaling pathway. Up-regulation of downstream nuclear proteins E2F3 and WSTF in immunoblots and microarrays along with their immunolocalization in the outer hair cells supported the pivotal role of p38/MAPK signaling in the mechanism underlying noise-induced hearing loss.

Death mode-dependent reduction in succinate dehydrogenase activity in hair cells of aging rat cochleae.

BACKGROUND: Our previous studies have shown that both apoptosis and necrosis are involved in hair cell (HC) pathogenesis in aging cochleae. To better understand the biological mechanisms responsible for the regulation of HC death, we examined the activity of succinate dehydrogenase (SDH), a mitochondrial bioenergetic enzyme, in the HCs of aging cochleae. METHODS: The auditory brainstem response thresholds elicited by tone bursts at 4, 10 and 20 kHz were measured in both young (2-3 months) and aging (22-23 months) Wistar rats. SDH activity was evaluated with a colorimetric assay using nitroblue tetrazolium monosodium salt. The SDH-labeled organs of Corti were double stained with propidium iodide, a DNA intercalating fluorescent probe for illustration of HC nuclei. All the specimens were examined with fluorescence microscopy and confocal microscopy. RESULTS: Aging rats exhibited a significant elevation of ABR thresholds with threshold shifts being 34 dB at 20 kHz, 28 dB at 10 kHz, and 25 dB at 4 kHz. Consistent with the reduction in the cochlear function, aging cochleae exhibited the reduction of SDH staining intensity in the apical and the basal ends of the cochleae, where a large number of apoptotic, necrotic, and missing HCs were evident. The reduction in SDH staining appeared in a cell-death-mode dependent fashion. Specifically, SDH labeling remained in apoptotic HCs. In contrast, SDH staining was markedly reduced or absent in necrotic HCs. CONCLUSIONS: In the aging cochlea, SDH activity is preserved in HCs undergoing apoptosis, but is substantially reduced in necrosis. These results suggest that mitochondrial energetic function is involved in the regulation of cell death pathways in the pathogenesis of aging cochleae.

Aging outer hair cells (OHCs) in the Fischer 344 rat cochlea: function and morphology.

As previously reported [Popelar, J., Groh, D., Pelanova, J., Canlon, B., Syka, J., 2006. Age-related changes in cochlear and brainstem auditory functions in Fischer 344 rats. Neurobiol. Aging 27, 490-500; Buckiova, D., Popelar, J., Syka, J., 2007. Aging cochleas in the F344 rat: morphological and functional changes. Exp. Gerontol. 42, 629-638; Bielefeld, E.C., Coling, D., Chen, G.D., Li, M.N., Tanaka, C., Hu, B.H., Henderson, D., 2008. Age-related hearing loss in the Fischer 344/NHsd rat substrain. Hear. Res. 241, 26-33], aged Fischer 344 (F344) rats with severe hearing loss retain many outer hair cells (OHCs) especially in the middle turn of the cochlea. The current study confirmed the previous findings showing that aged OHCs were present, but dysfunctional. Distortion product otoacoustic emissions (DPOAE), which are believed to reflect in vivo OHC motility, were absent in the aged rats while the majority of OHCs (>80%) were present and morphologically intact. There was no detectable injury of OHC stereocilia as assessed by actin-staining and examination under the light microscope. Cochlear microphonics (CM) at 12kHz, recorded from the middle turn, only showed a slight age-related reduction, indicating a normal mechanoelectrical transduction apparatus in the remaining OHCs in the cochlear regions with 10-20% OHC loss. Activities of succinate dehydrogenase (SDH), an enzyme shared by the citric acid cycle and the mitochondrial electron transport chain (METC), were also at normal levels in aged OHCs. Importantly, aged OHCs showed reduced levels of prestin immunolabeling compared to young controls. Together with our previous finding showing that the stria vascularis and endocochlear potential were essentially normal in aged F344 rats [Bielefeld, E.C., Coling, D., Chen, G.D., Li, M.N., Tanaka, C., Hu, B.H., Henderson, D., 2008. Age-related hearing loss in the Fischer 344/NHsd rat substrain. Hear. Res. 241, 26-33], the results suggest that disruption of prestin is the major cause of DPOAE loss and loss of cochlear sensitivity.