Uma das principais doenças degenerativas, conhecida internacionalmente pelo nome de osteoartrite (OA), é uma condição patológica crônica e prevalente que traz prejuízos sociais, psicológicos e financeiros a 10% da população em geral e a mais de 50% dos idosos. Acima dos 75 anos de idade aproximadamente 85% dos idosos são acometidos por essa doença. A população no Brasil envelhece rápido, envelhecerá em 30 anos tanto quanto a Europa envelheceu em 200 anos. Assim, novas técnicas para o tratamento da OA de joelho são muito relevantes. Este trabalho teve por objetivo estudar os efeitos de uma Terapia Combinada (TC) sobre o comportamento de ratos submetidos a um modelo experimental de osteoartrite de joelho. Ratos Wistar machos e adultos foram submetidos à lesão do joelho direito pela injeção intra-articular de iodoacetato monosódico (IM). Quinze dias após a lesão foram aplicados 3 tratamentos por 14 dias: Laserterapia de Baixa Potência (LBP), Estimulação Elétrica Artificial (EEA) e TC (i.e., LBP + EEA). Foram observados os efeitos agudos e crônicos destes tratamentos sobre o comportamento dos animais em 3 testes comportamentais: campo aberto, analgesímetro e descarga de peso. Os principais resultados do presente estudo indicam que (i) o modelo experimental de OA de joelho proposto foi induzido com sucesso e resultou em déficits agudos e crônicos ao longo de 30 dias de experimento; (ii) o tratamento com LBP resultou em diminuição dos déficits devido à hiperalgesia primária e secundária à lesão, porém não teve impacto sobre a funcionalidade geral do sistema de movimento dos animais; (iii) o treinamento com EEA resultou em diminuição dos déficits de hiperalgesia primária e teve impacto sobre a funcionalidade geral do sistema de movimento e (iv) a TC resultou em diminuição dos déficits de hiperalgesia primária e efeito moderado sobre a hiperalgesia secundária, além de impacto positivo sobre a funcionalidade geral do sistema de movimento. Com base nestes resultados, a TC apresentou efeitos benéficos tanto sobre o controle da dor, quanto para a menor incapacitação e melhor funcionalidade, sendo indicada para combater os efeitos deletérios da OA de joelho sobre o sistema de movimento. / A major degenerative disease, internationally known as osteoarthritis (OA) is a prevalent and chronic pathological condition which results in social, psychological and financial impairments to 10% of the general population and to over 50% of the elderly. Above 75 years of age approximately 85% of the elderly are affected by this disease. In Brazil there is a fast ageing of population who will age during 30 years as much as Europe aged in 200 years. Thus, new techniques for the treatment of knee OA are very relevant. This work aimed to study the effects of a combined therapy (TC) on the behavior of rats submitted to an experimental model of knee osteoarthritis. Male adult Wistar rats underwent right knee injury by intra-articular injection of monosodium iodoacetate (IM). Fifteen days after injury received 3 treatments for 14 days: Low Power Laser Therapy (LBP), Artificial Electrical Stimulation (EEA) and TC (i.e., LBP + EEA). We observed the acute and chronic effects of these treatments on the behavior of animals in 3 behavioral tests: open field, analgesymeter and weight bearing. The main results of this study indicate that (i) the proposed experimental model of knee OA was successfully induced and resulted in acute and chronic deficits over 30 days of experiment, (ii) treatment with LBP resulted in reduction of deficits due to primary and secondary hyperalgesia to the lesion, but had no impact on the overall functionality of the movement system, (iii) the training with EEA resulted in decreased deficits of primary hyperalgesia and impacted the overall functionality of the movement system (iv) the TC resulted in reduction of deficits due to primary hyperalgesia and moderate effect on secondary hyperalgesia, and positive impact on the overall functionality of the movement system. Based on these results, the TC showed beneficial effects on pain control and on less disability and better functionality, thus TC is indicated to combat the deleterious effects of knee OA on the motion system.

<p>Lead (Pb) is one of the most harmful and most abundant neurotoxins in the environment. Despite the extensive movement made to eradicate toxic levels of Pb in the environment, children, predominately in lower socioeconomic areas, are still exposed to varying levels of Pb. Human studies suggest that Pb exposure leads to altered drug consumption in adults by altering underlying neural mechanisms, specifically dopamine (DA) activity. However, there is limited research on this at blood Pb levels below 10 μg/dL, levels often seen in children growing up in neighborhoods located in old industrial and urban areas. To model how early-life low-level Pb exposure effects DA-dependent behaviors associated with addiction in adulthood, we used C57BL/6J mice. Litters were weaned at PND 21 and assigned to either a three-week history of 30 parts per million (ppm) Lead (IV) Acetate exposure or a control condition of 0 ppm Pb in DI drinking water. After the Pb exposure period, mice were switched to regular tap water until they reached adulthood. Afterward, separate animals were tested in one of three experiments: two-bottle choice alcohol preference drinking, alcohol-induced behavioral sensitization (EBS), and cocaine-induced behavioral sensitization (CBS). In experiment 1, our hypothesis was met, and both male and female mice with a prior Pb exposure displayed significantly higher alcohol intake and preference scores over the three-week period than control mice. In experiment 2, there were no differences in EBS and no evidence of EBS in any of the groups. However, there was an increased acute response to 2.0 g/kg EtOH in the Pb-exposed chronic group as compared to the control animals. Lastly, in experiment 3, Pb-exposed animals in the chronic cocaine group were more sensitive to the effects of cocaine (10 mg/kg) across days than the controls, both the acute cocaine groups and both saline control groups. Thus, with these experiments, we concluded that low levels of developmental Pb exposure might be targeting DA in the reward pathway, which is essential for alcohol intake and drug sensitization.</p>

Over 16 million people in the US suffer from major depressive disorder (MDD) each year. Approximately 1/3rd of MDD patients (~5 million) obtain only partial remission or no benefit after trials with multiple drugs or drug combinations. Recently, Ordway and colleagues have reportedelevated levels of DNA oxidation and upregulated gene expression of the base excision repair enzyme poly(ADP-ribose) polymerase-1 (PARP1) in postmortem brain from donors who had MDD at the time of death, as compared to age-matched psychiatrically normal control donors. This study was designed to test whether an inhibitor of PARP, 3-aminobenzamide (3-AB), may be effective to alleviate depressive-like behaviors in a rodent model of treatment-resistant depression. Male rats were ip administered lipopolysaccharide (LPS;100ug/kg) daily for 28 days, and administered a chronic unpredictable stressor on each day. All rats were also administered saline, 3-AB (40 mg/kg), or the serotonin-reuptake inhibitor (SSRI) fluoxetine (trade name: Prozac; 10 mg/kg) on each day, approximately 30 min after LPS treatment. During the 28 day period of LPS treatment, animals were behaviorally tested 5 times on sucrose preference (a test of anhedonia). At the end of the 28 day period, rats were behaviorally tested on a test of acute stress, the Porsolt swim test. Results revealed that 3-AB alleviated anhedonia and the response to acute stress in the Porsolt swim test superior to the fluoxetine group, demonstrating the utility of a PARP inhibitor to alleviate depressive-like behavior in this model. In addition, fluoxetine produced a loss of weight which recovered over days, but not to control levels, and 3-AB did not produce this effect. This study shows that PARP inhibitors may be effective in treatment-resistant depression.

<p>Humans are able to hear and detect small changes in sound across a wide dynamic range despite limited dynamic ranges of individual auditory nerve fibers. One mechanism that may adjust the dynamic range is the medial olivocochlear reflex (MOCR), a bilateral sound-activated system which decreases amplification of sound by the outer hair cells in the cochlea. Much of the previous physiological MOCR research has used long broadband noise elicitors. In behavioral measures of gain reduction, a fairly short elicitor has been found to be maximally effective for an on-frequency, tonal elicitor. However, the effect of the duration of broadband noise elicitors on behavioral tasks is unknown. Additionally, MOCR effects measured using otoacoustic emissions (OAEs), have not consistently shown a positive correlation with behavioral gain reduction tasks. This finding seems counterintuitive if both measurements share a common generation mechanism. The current study measured the effects of ipsilateral broadband noise elicitor duration on psychoacoustic gain reduction (Chapter 2) and transient-evoked OAEs (TEOAEs) (Chapter 3) estimated from a forward-masking paradigm. Changes in the TEOAE were measured in terms of magnitude and phase. When phase was accounted for in the TEOAEs, the time constants were approximately equal to the psychoacoustic time constants, and were relatively short (~80 ms). When only changes in TEOAE magnitude were measured, and phase was omitted, the average time constants were longer (~172-ms). Overall, the psychoacoustic and physiological data were consistent with the timecourse of gain reduction by the MOCR. However, when the magnitudes from these data were directly compared in a linear mixed-effects model (Chapter 4), no positive predictive relationship was found, and in some cases there was a significant negative association between the physiological and psychoacoustic measures of gain reduction as a function of elicitor duration. The multitude of factors involved in this relationship are discussed, as are the implications of dynamic range adjustment in everyday listening conditions (noisy backgrounds) in both normal and hearing impaired listeners (Chapter 5).</p>

<p dir="ltr">Previous research shows that the prevalence rates for alcohol use disorder, opioid use disorder, and chronic pain are high worldwide. Additional work has demonstrated that the most used pain medications are potentially addictive and not suitable for chronic use. Recent research suggests that inhibiting adenylyl cyclase type 1 (AC1) may be an alternative, non-addictive, method for reducing pain. The purpose of this study was to explore the effects of a novel AC1 inhibitor (CMPD84) on pain threshold and alcohol reward-related behavior in high-alcohol preferring male and female mice (HAP). No research to date has investigated the effects of AC1 inhibition on pain threshold and alcohol-induced conditioned place preference (CPP) in HAP mice, making this the first study to do so. Two manual von Frey experiments were run to explore the effects of CMPD84 (compared to alcohol and morphine) on pain threshold. Three CPP experiments were run to assess the effects of CMPD84 on the expression and acquisition of alcohol-induced CPP. Brain samples were taken from the NAc shell and vlPAG to assess levels of PKCε after the pain threshold experiments and the acquisition CPP experiment. PKCε has previously been shown to be linked to alcohol reward-behavior and pain relief. Results show that CMPD84 was more efficacious in increasing pain threshold in HAP mice compared to morphine and alcohol. CMPD84 also reduced the acquisition and expression of alcohol-induced CPP. AC1 inhibition reduced levels of PKCε in the brain, which matched behavioral results that reduced the expression and acquisition of alcohol-induced CPP, as well as increased pain threshold. These results suggest that PKCε may be linked to AC1 inhibition, pain threshold, and alcohol reward-related behaviors. </p>

<p>Persistent and maladaptive fear in the absence of a threat can be disruptive because it decreases an organism’s opportunity to seek life-sustaining substances. Learned safety signaling can suppress fear and encourage reward-seeking behavior, thus freeing the organism from fear induced immobilization. The infralimbic (IL) region of the prefrontal cortex is important for recalling fear extinction memories and for suppressing fear via learned safety signals. Neurons in the IL show an excitatory response to an extinguished fear cue. We thus hypothesized that neurons in the IL would encode safety by showing an excitatory response during active fear suppression to a learned safety signal. </p> <p>To assess global changes in IL activity, we monitored IL multi-unit activity to different cues while training animals in a fear-reward-safety discrimination task (Sangha, Chadick, & Janak, 2013). During the discrimination task, male rats learned that the reward cue predicted liquid sucrose, the fear cue predicted footshock and the joint presentation of both the fear and safety cues resulted in no footshock. We also counterbalanced the modality of fear and safety cues (auditory vs visual) with two separate groups of animals to control for potential sensory modality effects. Male rats showed high levels of freezing to the fear cue, and significantly reduced levels of freezing to the combined fear+safety cue. Male rats also showed high levels of port activity to the reward cue. There was no significant difference in the learning rate between the two counterbalanced conditions. </p> <p>Our multi-unit-data showed an increase in IL neuronal firing to the fear+safety cue across training sessions. This effect was consistent between the two counterbalanced conditions. We also examined single-unit activity from all animals that received light as the safety cue (n=8). This allowed us to examine the population response profile with a subset of the total animals. Although not statistically significant, our preliminary single-unit data demonstrated a decrease in the percentage of neurons that showed an inhibitory response to the fear+safety cue, but no change in the percentage of neurons that showed an excitatory response to the fear+safety cue. There was also no change in the magnitude of averaged firing rate in fear+safety excitatory or inhibitory neurons across training. Taken together, the decreased inhibition of single-unit activity in the IL may drive the increased excitation in multi-unit activity in the IL during behavioral fear suppression to a safety signal. </p>

<p>  </p> <p><em>Syngap1+/-</em> is a mouse mode for intellectual disability and autism spectrum disorder where haploinsufficiency of the <em>Syngap1</em> gene and therefore downregulation of SynGAP1 leads to early maturation of synapses within the brain within post-natal days fourteen and sixteen instead of at the normal developmental schedule of post-natal day thirty. This early-shifted timeline falls directly before the visual critical where binocular matching between inputs from the two eyes occurs, and during a period where neurons become selective to specific orientations. High-level visual and cognitive issues observed in autism spectrum disorder patients might follow from deficits in basic sensory processing development, but it is not yet understand how <em>Syngap1</em> haploinsufficiency affects visual development and visual processing. Therefore, to characterize visual processing within the <em>Syngap1+/-</em> mouse model of autism spectrum disorder, acute electrophysiological recordings were performed within the monocular and binocular regions of the mouse visual cortex (V1). Responses to a series of visual stimuli were analyzed to measure and compare receptive field size, orientation selectivity, and binocularity between <em>Syngap1+/-</em> mice and littermate controls. In order to understand how potential deficits in physiology could translate into visual perception, a behavioral training protocol was implemented which isolated visual acuity in mice. In accordance with known developmental timelines in the visual cortex, it was found that the receptive field sizes of V1 neurons in <em>Syngap1+/-</em> mice were unchanged from wild type controls. However, these same neurons had wider tuning curves and lower firing rates than neurons in littermate controls. Ocular dominance was unaltered between <em>Syngap1+/-</em> and wild type mice, but this was possibly due to low sample sizes of neurons from the binocular regions of V1. At the behavioral level, lower visual acuities were discovered in <em>Syngap1+/-</em> mice with a size degree difference compared to littermate controls – a minor but significant difference. These results indicate a reduction in SynGAP1 expression has a perceivable effect on V1 development and function at both physiological and behavioral levels.</p>

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