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Item Alcohol enhances unprovoked 22-28 kHz USVs and suppresses USV mean frequency in High Alcohol Drinking (HAD-1) male rats(Elsevier, 2016-04-01) Thakore, Neha; Reno, James M.; Gonzales, Rueben A.; Schallert, Timothy; Bell, Richard L.; Maddox, W. Todd; Duvauchelle, Christine L.; Department of Psychiatry, School of MedicineHeightened emotional states increase impulsive behaviors such as excessive ethanol consumption in humans. Though positive and negative affective states in rodents can be monitored in real-time through ultrasonic vocalization (USV) emissions, few animal studies have focused on the role of emotional status as a stimulus for initial ethanol drinking. Our laboratory has recently developed reliable, high-speed analysis techniques to compile USV data during multiple-hour drinking sessions. Since High Alcohol Drinking (HAD-1) rats are selectively bred to voluntarily consume intoxicating levels of alcohol, we hypothesized that USVs emitted by HAD-1 rats would reveal unique emotional phenotypes predictive of alcohol intake and sensitive to alcohol experience. In this study, male HAD-1 rats had access to water, 15% and 30% EtOH or water only (i.e., Controls) during 8 weeks of daily 7-h drinking-in-the-dark (DID) sessions. USVs, associated with both positive (i.e., 50-55 kHz frequency-modulated or FM) and negative (i.e., 22-28 kHz) emotional states, emitted during these daily DID sessions were examined. Findings showed basal 22-28 kHz USVs were emitted by both EtOH-Naïve (Control) and EtOH-experienced rats, alcohol experience enhanced 22-28 kHz USV emissions, and USV acoustic parameters (i.e., mean frequency in kHz) of both positive and negative USVs were significantly suppressed by chronic alcohol experience. These data suggest that negative affective status initiates and maintains excessive alcohol intake in selectively bred HAD-1 rats and support the notion that unprovoked emissions of negative affect-associated USVs (i.e., 22-28 kHz) predict vulnerability to excessive alcohol intake in distinct rodent models.Item Alcohol-preferring rats show decreased corticotropin-releasing hormone-2 receptor expression and differences in HPA activation compared to alcohol-nonpreferring rats(Wiley Blackwell (Blackwell Publishing), 2014-05) Yong, Weidong; Spence, John Paul; Eskay, Robert; Fitz, Stephanie D.; Damadzic, Ruslan; Lai, Dongbing; Foroud, Tatiana; Carr, Lucinda G.; Shekhar, Anantha; Chester, Julia A.; Heilig, Markus; Liang, Tiebing; Department of Medicine, IU School of MedicineBACKGROUND: Corticotropin-releasing hormone (CRH) and urocortins (UCNs) bind to corticotropin-releasing hormone type 2 receptor (CRF2 receptor ), a Gs protein-coupled receptor that plays an important role in modulation of anxiety and stress responses. The Crhr2 gene maps to a quantitative trait locus (QTL) for alcohol preference on chromosome 4 previously identified in inbred alcohol-preferring (iP) and-nonpreferring (iNP) F2 rats. METHODS: Real-time polymerase chain reaction was utilized to screen for differences in Crhr2 mRNA expression in the central nervous system (CNS) of male iP and iNP rats. DNA sequence analysis was then performed to screen for polymorphism in Crhr2 in order to identify genetic variation, and luciferase reporter assays were then applied to test their functional significance. Next, binding assays were used to determine whether this polymorphism affected CRF2 receptor binding affinity as well as CRF2 receptor density in the CNS. Finally, social interaction and corticosterone levels were measured in the P and NP rats before and after 30-minute restraint stress. RESULTS: Crhr2 mRNA expression studies found lower levels of Crhr2 mRNA in iP rats compared to iNP rats. In addition, DNA sequencing identified polymorphisms in the promoter region, coding region, and 3'-untranslated region between the iP and iNP rats. A 7 bp insertion in the Crhr2 promoter of iP rats altered expression in vitro as measured by reporter assays, and we found that CRF2 receptor density was lower in the amygdala of iP as compared to iNP rats. Male P rats displayed decreased social interaction and significantly higher corticosterone levels directly following 30-minute restraint when compared to male NP rats. CONCLUSIONS: This study identified Crhr2 as a candidate gene of interest underlying the chromosome 4 QTL for alcohol consumption that was previously identified in the P and NP model. Crhr2 promoter polymorphism is associated with reduced mRNA expression in certain brain regions, particularly the amygdala, and lowered the density of CRF2 receptor in the amygdala of iP compared to iNP rats. Together, these differences between the animals may contribute to the drinking disparity as well as the anxiety differences of the P and NP rats.Item The auditory steady-state response (ASSR): a translational biomarker for schizophrenia(Elsevier, 2013) O'Donnell, Brian F.; Vohs, Jenifer L.; Krishnan, Giri P.; Rass, Olga; Hetrick, William P.; Morzorati, Sandra L.; Department of Psychiatry, IU School of MedicineElectrophysiological methods have demonstrated disturbances of neural synchrony and oscillations in schizophrenia which affect a broad range of sensory and cognitive processes. These disturbances may account for a loss of neural integration and effective connectivity in the disorder. The mechanisms responsible for alterations in synchrony are not well delineated, but may reflect disturbed interactions within GABAergic and glutamatergic circuits, particularly in the gamma range. Auditory steady-state responses (ASSRs) provide a non-invasive technique used to assess neural synchrony in schizophrenia and in animal models at specific response frequencies. ASSRs are electrophysiological responses entrained to the frequency and phase of a periodic auditory stimulus generated by auditory pathway and auditory cortex activity. Patients with schizophrenia show reduced ASSR power and phase locking to gamma range stimulation. We review alterations of ASSRs in schizophrenia, schizotypal personality disorder, and first-degree relatives of patients with schizophrenia. In vitro and in vivo approaches have been used to test cellular mechanisms for this pattern of findings. This translational, cross-species approach provides support for the role of N-methyl-D-aspartate and GABAergic dysregulation in the genesis of perturbed ASSRs in schizophrenia and persons at risk.Item Biomechanics of head impacts associated with diagnosed concussion in female collegiate ice hockey players(Elsevier, 2015-07-16) Wilcox, Bethany J.; Beckwith, Jonathan G.; Greenwald, Richard M.; Raukar, Neha P.; Chu, Jeffrey J.; McAllister, Thomas W.; Flashman, Laura A.; Maerlender, Arthur C.; Duhaime, Ann-Christine; Crisco, Joseph J.; Department of Psychiatry, IU School of MedicineEpidemiological evidence suggests that female athletes may be at a greater risk of concussion than their male counterparts. The purpose of this study was to examine the biomechanics of head impacts associated with diagnosed concussions in a cohort of female collegiate ice hockey players. Instrumented helmets were worn by 58 female ice hockey players from 2 NCAA programs over a three year period. Kinematic measures of single impacts associated with diagnosed concussion and head impact exposure on days with and without diagnosed concussion were evaluated. Nine concussions were diagnosed. Head impact exposure was greater in frequency and magnitude on days of diagnosed concussions than on days without diagnosed concussion for individual athletes. Peak linear accelerations of head impacts associated with diagnosed concussion in this study are substantially lower than those previously reported in male athletes, while peak rotational accelerations are comparable. Further research is warranted to determine the extent to which female athletes' biomechanical tolerance to concussion injuries differs from males.Item CaMKII Controls Whether Touch Is Painful(Society for Neuroscience, 2015-10-21) Yu, Hongwei; Pan, Bin; Weyer, Andy; Wu, Hsiang-En; Meng, Jingwei; Fischer, Gregory; Vilceanu, Daniel; Light, Alan R.; Stucky, Cheryl; Rice, Frank L.; Hudmon, Andy; Hogan, Quinn; Department of Biochemistry & Molecular Biology, IU School of MedicineThe sensation of touch is initiated when fast conducting low-threshold mechanoreceptors (Aβ-LTMRs) generate impulses at their terminals in the skin. Plasticity in this system is evident in the process of adaption, in which a period of diminished sensitivity follows prior stimulation. CaMKII is an ideal candidate for mediating activity-dependent plasticity in touch because it shifts into an enhanced activation state after neuronal depolarizations and can thereby reflect past firing history. Here we show that sensory neuron CaMKII autophosphorylation encodes the level of Aβ-LTMR activity in rat models of sensory deprivation (whisker clipping, tail suspension, casting). Blockade of CaMKII signaling limits normal adaptation of action potential generation in Aβ-LTMRs in excised skin. CaMKII activity is also required for natural filtering of impulse trains as they travel through the sensory neuron T-junction in the DRG. Blockade of CaMKII selectively in presynaptic Aβ-LTMRs removes dorsal horn inhibition that otherwise prevents Aβ-LTMR input from activating nociceptive lamina I neurons. Together, these consequences of reduced CaMKII function in Aβ-LTMRs cause low-intensity mechanical stimulation to produce pain behavior. We conclude that, without normal sensory activity to maintain adequate levels of CaMKII function, the touch pathway shifts into a pain system. In the clinical setting, sensory disuse may be a critical factor that enhances and prolongs chronic pain initiated by other conditions. SIGNIFICANCE STATEMENT: The sensation of touch is served by specialized sensory neurons termed low-threshold mechanoreceptors (LTMRs). We examined the role of CaMKII in regulating the function of these neurons. Loss of CaMKII function, such as occurred in rats during sensory deprivation, elevated the generation and propagation of impulses by LTMRs, and altered the spinal cord circuitry in such a way that low-threshold mechanical stimuli produced pain behavior. Because limbs are protected from use during a painful condition, this sensitization of LTMRs may perpetuate pain and prevent functional rehabilitation.Item A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease(Elsevier, 2014-11) Jessen, Frank; Amariglio, Rebecca E.; van Boxtel, Martin; Breteler, Monique; Ceccaldi, Mathieu; Chételat, Gaël; Dubois, Bruno; Dufouil, Carole; Ellis, Kathryn A.; van der Flier, Wiesje M.; Glodzik, Lidia; van Harten, Argonde C.; de Leon, Mony J.; McHugh, Pauline; Mielke, Michelle M.; Molinuevo, Jose Luis; Mosconi, Lisa; Osorio, Ricardo S.; Perrotin, Audrey; Petersen, Ronald C.; Rabin, Laura A.; Rami, Lorena; Reisberg, Barry; Rentz, Dorene M.; Sachdev, Perminder S.; de la Sayette, Vincent; Saykin, Andrew J.; Scheltens, Philip; Shulman, Melanie B.; Slavin, Melissa J.; Sperling, Reisa A.; Stewart, Robert; Uspenskaya, Olga; Vellas, Bruno; Visser, Pieter Jelle; Wagner, Michael; Department of Radiology and Imaging Sciences, IU School of MedicineThere is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimer's disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD-I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre-mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus.Item Cortical PKC inhibition promotes axonal regeneration of the corticospinal tract and forelimb functional recovery after cervical dorsal spinal hemisection in adult rats(Oxford University Press, 2014-11) Wang, Xiaofei; Hu, Jianguo; She, Yun; Smith, George M.; Xu, Xiao-Ming; Department of Neurological Surgery, IU School of MedicineOur previous study shows that conventional protein kinases C (cPKCs) are key signaling mediators that are activated by extracellular inhibitory molecules. Inhibition of cPKC by intrathecal infusion of a cPKC inhibitor, GÖ6976, into the site of dorsal hemisection (DH) induces regeneration of lesioned dorsal column sensory, but not corticospinal tract (CST), axons. Here, we investigated whether a direct cortical delivery of GÖ6976 into the soma of corticospinal neurons promotes regeneration of CST and the recovery of forelimb function in rats with cervical spinal cord injuries. We report that cortical delivery of GÖ6976 reduced injury-induced activation of conventional PKCα and PKCβ1 in CST neurons, promoted regeneration of CST axons through and beyond a cervical DH at C4, formed new synapses on target neurons caudal to the injury, and enhanced forelimb functional recovery in adult rats. When combined with lenti-Chondroitinase ABC treatment, cortical administration of GÖ6976 promoted even greater CST axonal regeneration and recovery of forelimb function. Thus, this study has demonstrated a novel strategy that can promote anatomical regeneration of damaged CST axons and partial recovery of forelimb function. Importantly, such an effect is critically dependent on the efficient blockage of injury-induced PKC activation in the soma of layer V CST neurons.Item Delayed Effects of Acute Radiation Exposure in a Murine Model of the H-ARS: Multiple-Organ Injury Consequent to <10 Gy Total Body Irradiation(Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2015-11) Unthank, Joseph L.; Miller, Steven J.; Quickery, Ariel K.; Ferguson, Ethan L.; Wang, Meijing; Sampson, Carol H.; Chua, Hui Lin; DiStasi, Matthew R.; Feng, Hailin; Fisher, Alexa; Katz, Barry P.; Plett, P. Artur; Sandusky, George E.; Sellamuthu, Rajendran; Vemula, Sasidhar; Cohen, Eric P.; MacVittie, Thomas J.; Orschell, Christie M.; Department of Surgery, School of MedicineThe threat of radiation exposure from warfare or radiation accidents raises the need for appropriate animal models to study the acute and chronic effects of high dose rate radiation exposure. The goal of this study was to assess the late development of fibrosis in multiple organs (kidney, heart, and lung) in survivors of the C57BL/6 mouse model of the hematopoietic-acute radiation syndrome (H-ARS). Separate groups of mice for histological and functional studies were exposed to a single uniform total body dose between 8.53 and 8.72 Gy of gamma radiation from a Cs radiation source and studied 1-21 mo later. Blood urea nitrogen levels were elevated significantly in the irradiated mice at 9 and 21 mo (from ∼22 to 34 ± 3.8 and 69 ± 6.0 mg dL, p < 0.01 vs. non-irradiated controls) and correlated with glomerosclerosis (29 ± 1.8% vs. 64 ± 9.7% of total glomeruli, p < 0.01 vs. non-irradiated controls). Glomerular tubularization and hypertrophy and tubular atrophy were also observed at 21 mo post-total body irradiation (TBI). An increase in interstitial, perivascular, pericardial and peribronchial fibrosis/collagen deposition was observed from ∼9-21 mo post-TBI in kidney, heart, and lung of irradiated mice relative to age-matched controls. Echocardiography suggested decreased ventricular volumes with a compensatory increase in the left ventricular ejection fraction. The results indicate that significant delayed effects of acute radiation exposure occur in kidney, heart, and lung in survivors of the murine H-ARS TBI model, which mirrors pathology detected in larger species and humans at higher radiation doses focused on specific organs.Item Dental maturity of Caucasian children in the Indianapolis area(American Academy of Pediatric Dentistry, 2011-05) Weddell, Lauren S.; Hartsfield, James K.; Department of Pediatric Dentistry, School of DentistryPURPOSE: The purpose of this study was to compare chronologic and dental age using Demirjian's method. METHODS: Two hundred and fifty-seven panoramic radiographs of healthy 5- to 17.5-year-old Caucasian children in the Indianapolis area were evaluated using Demirjian's 7 tooth method. RESULTS: The intraclass correlation coefficient (ICC) for agreement with Demirjian was 0.94 (95% confidence interval [CI]: 0.87, 0.97). The ICC for repeatability of the investigator was 0.97 (95% CI=0.95, 0.99). Calculated dental age was significantly greater than chronologic age by 0.59 years (P<.001). There was no significant difference in the mean difference in ages between sexes (P=.73). Medicaid subjects had a significantly higher (P<.001) mean difference (0.82 years) than private insurance subjects (0.32 years). There was a significant negative correlation between the chronologic age and the difference in ages (r=-0.29, P<.001). Overweight (P<.001) and obese (P=.004) subjects were significantly more dentally advanced than normal (P=.35) and underweight (P=.42) subjects. CONCLUSIONS: Demirjian's method has high inter- and intraexaminer repeatability. Caucasian children in the Indianapolis area are more advanced dentally than the French-Canadian children studied by Demirjian. Difference between dental age and chronologic age varies depending on the age of the child, socioeconomic status, and body mass index.Item Depressed basal hypothalamic neuronal activity in type-1 diabetic mice is correlated with proinflammatory secretion of HMBG1(Elsevier, 2016-02-26) Thinschmidt, Jeffrey S.; Colon-Perez, Luis M.; Febo, Marcelo; Caballero, Sergio; King, Michael A.; White, Fletcher A.; Grant, Maria B.; Department of Ophthalmology, School of MedicineWe recently found indicators of hypothalamic inflammation and neurodegeneration linked to the loss of neuroprotective factors including insulin-like growth factor (IGF-1) and IGF binding protein-2 (IGFBP-3) in mice made diabetic using streptozotocin (STZ). In the current work, a genetic model of type-1 diabetes (Ins2(Akita) mouse) was used to evaluate changes in neuronal activity and concomitant changes in the proinflammatory mediator high-mobility group box-1 (HMBG1). We found basal hypothalamic neuronal activity as indicated by manganese-enhanced magnetic resonance imaging (MEMRI) was significantly decreased in 8 months old, but not 2 months old Ins2(Akita) diabetic mice compared to controls. In tissue from the same animals we evaluated the expression of HMBG1 using immunohistochemistry and confocal microscopy. We found decreased HMBG1 nuclear localization in the paraventricular nucleus of the hypothalamus (PVN) in 8 months old, but not 2 months old diabetic animals indicating nuclear release of the protein consistent with an inflammatory state. Adjacent thalamic regions showed little change in HMBG1 nuclear localization and neuronal activity as a result of diabetes. This work extends our previous findings demonstrating changes consistent with hypothalamic neuroinflammation in STZ treated animals, and shows active inflammatory processes are correlated with changes in basal hypothalamic neuronal activity in Ins2(Akita) mice.