Effects of thyroxine treatment on histology and behavior using the methimazole model of congenital hypothyroidism in the rat

The timing of thyroxine (T4) replacement treatment in congenital hypothyroidism (CH) has been suggested to be important for optimizing cognitive recovery in humans; however this has not been fully established using modern animal models of CH. Consequently, the current studies investigated the ameliorating effects of postnatal T4 treatment on neuropathology and behavior in CH rats. Rat dams were administered methimazole to produce CH offspring, then brain tissue from male CH pups was analyzed to determine the effects of postnatal (P3, P7, P14 and P21) T4 treatment on hippocampal dendritic branching and the expression of nerve growth factor (NGF). Two operant behavioral procedures were employed to confirm and extend previous findings obtained using this model, and to investigate timelines for instigating T4 treatment on improved behavioral outcomes. T4 treatment initiated at P14 was protective of a reduction in dendritic branching in the hippocampus, and initiated at P7 was protective of a reduction of NGF expression in the fimbria of the hippocampus. Induction of CH did not affect the acquisition of simple operant response rules but had a significant effect on the acquisition of complex operant rules subsequently imposed. Furthermore, T4 treatment initiated at P3 protected learning deficits seen following the imposition of complex operant response rules. These findings indicate T4 treatment initiated at P7 is sufficient for the protection of hippocampal NGF expression and dendritic branching but for the protection of complex behavioral abilities T4 treatment is necessary prior to or approximating P3.

Supressão condicionada com diferentes estímulos aversivos: choque elétrico e jato de ar quente

Um estímulo neutro, quando pareado a um estímulo aversivo incondicional, adquire a função de aversivo (condicional) e, indiretamente, também é capaz de suprimir operantes. Tal fenômeno foi denominado de “supressão condicionada” e está principalmente relacionado a certos estados emocionais, como a ansiedade. A literatura mostra que, em geral, o estímulo aversivo incondicional utilizado se restringe ao choque elétrico. Foram poucos os estímulos aversivos alternativos testados que se mostraram eficazes. Entretanto, mesmo utilizando o choque como aversivo incondicional, há outras variáveis que podem influenciar diretamente o surgimento do fenômeno. Este trabalho teve por objetivo examinar e comparar a produção de supressão condicionada com dois tipos de estímulos aversivos: jato de ar quente (JAQ) e choque elétrico. Foram utilizados 4 ratos albinos (Rattus norvegicus, Wistar). Duas Caixas de Condicionamento Operante, uma utilizada para o estímulo choque e a outra adaptada para o JAQ, serviram de equipamentos. Os sujeitos foram divididos em duplas e expostos a pareamentos de um estímulo neutro com diferentes estímulos aversivos: Som+JAQ (Sujeito J1 e J2) e Som+Choque elétrico (Sujeito C1 e C2). Os dados mostram que os sujeitos expostos ao delineamento com choque apresentaram uma razão supressiva total (0,0) após dois (C1) ou três (C2) pareamentos, o que significa que o som tornou-se um aversivo condicional capaz de suprimir integralmente a freqüência da resposta de pressão à barra (RPB). Já para os sujeitos expostos ao procedimento com JAQ ocorreu somente supressão parcial da RPB frente ao som, sendo necessárias no mínimo oito (J1) e sete (J2) pareamentos para que os valores da razão supressiva chegassem a 0,5 (J1) e 0,2 (J2). As análises de outras respostas mostraram que em média ocorreu um aumento de 83,3% (J1) e 275% (J2) na frequência das respostas exploratórias durante a apresentação do som, nas sessões de pareamento com o JAQ, comparado com a apresentação do som nas sessões de habituação, enquanto que para os sujeitos que foram expostos ao pareamento com o choque houve uma supressão de 44,2% (C1) e 57,1% (C2) em tais respostas. Tais dados permitem concluir que a supressão ocasionada pelo pareamento do som+choque atingiu outras classes de respostas, diferente do som pareado com o JAQ. A supressão ocasionada pelo JAQ parece ter sido conseqüência da emissão de respostas exploratórias. É possível que o parâmetro intensidade do JAQ, utilizado neste experimento, tenha sido a variável responsável por tais resultados. Futuras pesquisas poderão elucidar estes dados.

THE NEGATIVE EFFECTS OF ALCOHOL HANGOVER ON HIGH-ANXIETY PHENOTYPE RATS ARE INFLUENCED BY THE GLUTAMATE RECEPTORS OF THE DORSAL MIDBRAIN

Alcoholism is a chronic disorder characterized by the appearance of a withdrawal syndrome following the abrupt cessation of alcohol intake that includes symptoms of physical and emotional disturbances, anxiety being the most prevalent symptom. In humans, it was shown that anxiety may increase the probability of relapse. In laboratory animals, however, the use of anxiety to predict alcohol preference has remained difficult. Excitatory amino acids as glutamate have been implicated in alcohol hangover and may be responsible for the seizures and anxiety observed during withdrawal. The dorsal periaqueductal gray (DPAG) is a midbrain region critical for the modulation/expression of anxiety- and fear-related behaviors and the propagation of seizures induced by alcohol withdrawal, the glutamate neurotransmission being one of the most affected. The present study was designed to evaluate whether low- (LA) and high-anxiety rats (HA), tested during the alcohol hangover phase, in which anxiety is the most prevalent symptom, are more sensitive to the reinforcing effects of alcohol when tested in a voluntary alcohol drinking procedure. Additionally, we were interested in investigating the main effects of reducing the excitatory tonus of the dorsal midbrain, after the blockade of the ionotropic glutamate receptors into the DPAG, on the voluntary alcohol intake of HA and LA motivated rats that were made previously experienced with the free operant response of alcohol drinking. For this purpose, we used local infusions of the N-metil D-Aspartato (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-kainate receptors antagonist DL-2-Amino-7-phosphonoheptanoic acid - DL-AP7 (10 nmol/0.2 mu l) and L-glutamic acid diethyl ester - GDEE (160 nmol/0.2 mu l) respectively. Alcohol intoxication was produced by 10 daily bolus intraperitonial (IP) injections of alcohol (2.0 g/kg). Peak-blood alcohol levels were determined by gas-chromatography analysis in order to assess blood-alcohol content. Unconditioned and conditioned anxiety-like behavior was assessed by the use of the fear-potentiated startle procedure (FPS). Data collected showed that anxiety and alcohol drinking in HA animals are positively correlated in animals that were made previously familiarized with the anxiolytic effects of alcohol. In addition, anxiety-like behavior induced during alcohol hangover seems to be an effect of changes in glutamatergic neurotransmission into DPAG possibly involving AMPA/kainate and NMDA receptors, among others. (C) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.

Effects of drugs that potentiate GABA on extinction of positively-reinforced operant behaviour

Extinction following positively reinforced operant conditioning reduces response frequency, at least in part through the aversive or frustrative effects of non-reinforcement. According to J.A. Gray's theory, non-reinforcement activates the behavioural inhibition system which in turn causes anxiety. As predicted, anxiolytic drugs including benzodiazepines affect the operant extinction process. Recent studies have shown that reducing GABA-mediated neurotransmission retards extinction of aversive conditioning. We have shown in a series of studies that anxiolytic compounds that potentiate GABA facilitate extinction of positively reinforced fixed-ratio operant behaviour in C57B1/6 male mice. This effect does not occur in the early stages of extinction, nor is it dependent on cumulative effects of the compound administered. Potentiation of GABA at later stages has the effect of increasing sensitivity to the extinction contingency and facilitates the inhibition of the behaviour that is no longer required. The GABAergic hypnotic, zolpidem, has the same selective effects on operant extinction in this procedure. The effects of zolpidem are not due to sedative action. There is evidence across our series of experiments that different GABA-A subtype receptors are involved in extinction facilitation and anxiolysis. Consequently, this procedure may not be an appropriate model for anxiolytic drug action, but it may be a useful technique for analysing the neural bases of extinction and designing therapeutic interventions in humans where failure to extinguish inappropriate behaviours can lead to pathological conditions such as post-traumatic stress disorder.

Operant measurement of auditory threshold in prelingually deaf users of cochlear implants: II

Two experiments evaluated an operant procedure for establishing stimulus control using auditory and electrical stimuli as a baseline for measuring the electrical current threshold of electrodes implanted in the cochlea. Twenty-one prelingually deaf children, users of cochlear implants, learned a Go/No Go auditory discrimination task (i.e., pressing a button in the presence of the stimulus but not in its absence). When the simple discrimination baseline became stable, the electrical current was manipulated in descending and ascending series according to an adapted staircase method. Thresholds were determined for three electrodes, one in each location in the cochlea (basal, medial, and apical). Stimulus control was maintained within a certain range of decreasing electrical current but was eventually disrupted. Increasing the current recovered stimulus control, thus allowing the determination of a range of electrical currents that could be defined as the threshold. The present study demonstrated the feasibility of the operant procedure combined with a psychophysical method for threshold assessment, thus contributing to the routine fitting and maintenance of cochlear implants within the limitations of a hospital setting.

Novelty, but Not Operant Aversive Learning, Enhances Fos and Egr-1 Expression in the Medial Prefrontal Cortex and Hippocampal Areas of Rats

Immediate early genes (IEG) are presumed to be activated in response to stress, novelty, and learning. Evidence supports the involvement of prefrontal and hippocampal areas in stress and learning, but also in the detection of novel events. This study examined whether a previous experience with shocks changes the pattern of Fos and Egr-1 expression in the medial prefrontal cortex (mPFC), the hippocampal cornus ammonis 1 (CA1), and dentate gyrus (DG) of adult male Wistar rats that learned to escape in an operant aversive test. Subjects previously exposed to inescapable footshocks that learned to escape from Shocks were assigned to the treated group (EXP). Subjects from Group Novelty (NOV) rested undisturbed during treatment and also learned to escape in the test. The nonshock group (NSH) rested undisturbed in both sessions. Standard immunohistochemistry procedures were used to detect the proteins in brain sections. The results show that a previous experience with shocks changed the pattern of IEG expression, then demonstrating c-fos and egr-1 induction as experience-dependent events. Compared with NSH and EXP an enhanced Fos expression was detected in the mPFC and CA1 subfield of Group NOV, which also exhibited increased Egr-1 expression in the mPFC and DG in comparison to NSH. No differences were found in the DG for Fos, or in the CA1 for Egr-1. Novelty, and not the operant aversive escape learning, seems to have generated IEG induction. The results suggest novel stimuli as a possible confounding factor in studies on Fos and/or Egr-1 expression in aversive conditions.

Cellular mechanisms of operant and classical conditioning

The ability to associate a predictive stimulus with a subsequent salient event (i.e., classical conditioning) and the ability to associate an expressed behavior with the consequences (i.e., operant conditioning) allow for a predictive understanding of a changing environment. Although they are operationally distinct, there has been considerable debate whether at some fundamental level classical and operant conditioning are mechanistically distinct or similar. Feeding behavior of Aplysia (i.e., biting) was chosen as the model system and was successfully conditioned with appetitive forms of both operant and classical conditioning. The neuronal circuitry responsible for feeding is well understood and is suitable for cellular analyses, thus providing for a mechanistic comparison between these two forms of associative learning. ^ Neuron B51 is part of the feeding circuitry of Aplysia and is critical for the expression of ingestive behaviors. B51 also is a locus of plasticity following both operant and classical conditioning. Both in vivo and in vitro operant conditioning increased the input resistance and the excitability of B51. No pairing-specific changes in the input resistance were observed following both in vivo and in vitro classical conditioning. However, classical conditioning decreased the excitability of B51. Thus, both operant and classical conditioning modified the threshold level for activation of neuron B51, but in opposite directions, revealing key differences in the cellular mechanisms underlying these two forms of associative learning. ^ Next, the cellular mechanisms underlying operant conditioning were investigated in more detail using a single-cell analogue. The single-cell analogue successfully recapitulated the previous in vivo and in vitro operant conditioning results by increasing the input resistance and the excitability of B51. Both PKA and PKC were necessary for operant conditioning. Dopamine appears to be the transmitter mediating the reinforcement signal in this form of conditioning. A D1 dopamine receptor antibody revealed that the D1receptor localizes to the axon hillock, which is also the region that gives the strongest response when iontophoresing dopamine. ^ The studies presented herein, thus, provide for a greater understanding of the mechanisms underlying both of these forms of associative learning and demonstrate that they likely operate through distinct cellular mechanisms. ^

Operant and respondent procedures to establish social stimuli as reinforcers in children with autism

According to the DSM-IV- TR (American Psychiatric Association, 2000), one of the core deficits in autism is in the impairment of social interaction. Some have suggested that underlying these deficits is the reality that individuals with autism do not find social stimuli to be as reinforcing as other types of stimuli (Dawson, 2008). An interesting and growing body of literature supports the notion that symptoms in autism may be caused by a general reduction in social motivation (Chevallier et al., 2012). A review of the literature suggests that social orienting and social motivation are low in individuals with autism, and including social motivation as a target for therapeutic intervention should be pursued (Helt et al., 2008). Through our understanding of learning processes, researchers in behavior analysis and related fields have been able to use conditioning procedures to change the function of neutral or ineffective stimuli, including tokens (Ayllon & Azrin, 1968), facial expressions (Gewirtz & Pelaez-Nogueras, 1992) and praise (Dozier et al., 2012). The current study aimed to use operant and respondent procedures to condition social stimuli that were empirically shown to not be reinforcing prior to conditioning. Further, this study aimed to compare the two procedures in their effectiveness to condition social stimuli to function as reinforcers, and in their maintenance of effects over time. Using a multiple-baseline, multi-element design, one social stimulus was conditioned under each procedure to compare the different response rates following conditioning. Finally, the study sought to determine if conditioning social stimuli to function as reinforcers had any effect on the social functioning of young children with autism. Six children diagnosed with autism between the ages of 18 months and 3 years participated. Results show that the respondent procedure (pairing) resulted in more robust and enduring effects than the operant procedure (Sd procedure). Results of a social communication assessment (ESCS, Mundy et al., 2003) before and after conditioning demonstrate gains in all areas of social communication, particularly in the areas of initiating and responding to joint attention.^

Operant and Respondent Procedures to Establish Social Stimuli as Reinforcers in Children with Autism

According to the DSM-IV- TR (American Psychiatric Association, 2000), one of the core deficits in autism is in the impairment of social interaction. Some have suggested that underlying these deficits is the reality that individuals with autism do not find social stimuli to be as reinforcing as other types of stimuli (Dawson, 2008). An interesting and growing body of literature supports the notion that symptoms in autism may be caused by a general reduction in social motivation (Chevallier et al., 2012). A review of the literature suggests that social orienting and social motivation are low in individuals with autism, and including social motivation as a target for therapeutic intervention should be pursued (Helt et al., 2008). Through our understanding of learning processes, researchers in behavior analysis and related fields have been able to use conditioning procedures to change the function of neutral or ineffective stimuli, including tokens (Ayllon & Azrin, 1968), facial expressions (Gewirtz & Pelaez-Nogueras, 1992) and praise (Dozier et al., 2012). The current study aimed to use operant and respondent procedures to condition social stimuli that were empirically shown to not be reinforcing prior to conditioning. Further, this study aimed to compare the two procedures in their effectiveness to condition social stimuli to function as reinforcers, and in their maintenance of effects over time. Using a multiple-baseline, multi-element design, one social stimulus was conditioned under each procedure to compare the different response rates following conditioning. Finally, the study sought to determine if conditioning social stimuli to function as reinforcers had any effect on the social functioning of young children with autism. Six children diagnosed with autism between the ages of 18 months and 3 years participated. Results show that the respondent procedure (pairing) resulted in more robust and enduring effects than the operant procedure (Sd procedure). Results of a social communication assessment (ESCS, Mundy et al., 2003) before and after conditioning demonstrate gains in all areas of social communication, particularly in the areas of initiating and responding to joint attention.