The role of the Ventral Nucleus of the Trapezoid Body in the auditory prepulse inhibition of the acoustic startle reflex.

Cholinergic signaling is essential to mediate the auditory prepulse inhibition (PPI), an operational measure of sensorimotor gating, that refers to the reduction of the acoustic startle reflex (ASR) when a low-intensity, non-startling acoustic stimulus (the prepulse) is presented just before the onset of the acoustic startle stimulus. The cochlear root neurons (CRNs) are the first cells of the ASR circuit to receive cholinergic inputs from non-olivocochlear neurons of the ventral nucleus of the trapezoid body (VNTB) and subsequently decrease their neuronal activity in response to auditory prepulses. Yet, the contribution of the VNTB-CRNs pathway to the mediation of PPI has not been fully elucidated. In this study, we used the immunotoxin anti-choline acetyltransferase (ChAT)-saporin as well as electrolytic lesions of the medial olivocochlear bundle to selectively eliminate cholinergic VNTB neurons, and then assessed the ASR and PPI paradigms. Retrograde track-tracing experiments were conducted to precisely determine the site of lesioning VNTB neurons projecting to the CRNs. Additionally, the effects of VNTB lesions and the integrity of the auditory pathway were evaluated via auditory brain responses tests, ChAT- and FOS-immunohistochemistry. Consequently, we established three experimental groups: 1) intact control rats (non-lesioned), 2) rats with bilateral lesions of the olivocochlear bundle (OCB-lesioned), and 3) rats with bilateral immunolesions affecting both the olivocochlear bundle and the VNTB (OCB/VNTB-lesioned). All experimental groups underwent ASR and PPI tests at several interstimulus intervals before the lesion and 7, 14, and 21 days after it. Our results show that the ASR amplitude remained unaffected both before and after the lesion across all experimental groups, suggesting that the VNTB does not contribute to the ASR. The%PPI increased across the time points of evaluation in the control and OCB-lesioned groups but not in the OCB/VNTB-lesioned group. At the ISI of 50 ms, the OCB-lesioned group exhibited a significant increase in%PPI (p < 0.01), which did not occur in the OCB/VNTB-lesioned group. Therefore, the ablation of cholinergic non-olivocochlear neurons in the OCB/VNTB-lesioned group suggests that these neurons contribute to the mediation of auditory PPI at the 50 ms ISI through their cholinergic projections to CRNs. Our study strongly reinforces the notion that auditory PPI encompasses a complex mechanism of top-down cholinergic modulation, effectively attenuating the ASR across different interstimulus intervals within multiple pathways.

Overexpression of the immediate-early genes Egr1, Egr2, and Egr3 in two strains of rodents susceptible to audiogenic seizures.

Genetic animal models of epilepsy are an important tool for further understanding the basic cellular mechanisms underlying epileptogenesis and for developing novel antiepileptic drugs. We conducted a comparative study of gene expression in the inferior colliculus, a nucleus that triggers audiogenic seizures, using two animal models, the Wistar audiogenic rat (WAR) and the genetic audiogenic seizure hamster (GASH:Sal). For this purpose, both models were exposed to high intensity auditory stimulation, and 60min later, the inferior colliculi were collected. As controls, intact Wistar rats and Syrian hamsters were subjected to stimulation and tissue preparation protocols identical to those performed on the experimental animals. Ribonucleic acid was isolated, and microarray analysis comparing the stimulated Wistar and WAR rats showed that the genomic profile of these animals displayed significant (fold change, |FC|≥2.0 and p<0.05) upregulation of 38 genes and downregulation of 47 genes. Comparison of gene expression profiles between stimulated control hamsters and stimulated GASH:Sal revealed the upregulation of 10 genes and the downregulation of 5 genes. Among the common genes that were altered in both models, we identified the zinc finger immediate-early growth response gene Egr3. The Egr3 protein is a transcription factor that is induced by distinct stress-elicited factors. Based on immunohistochemistry, this protein was expressed in the cochlear nucleus complex, the inferior colliculus, and the hippocampus of both animal models as well as in lymphoma tumors of the GASH:Sal. Our results support that the overexpression of the Egr3 gene in both models might contribute to neuronal viability and development of lymphoma in response to stress associated with audiogenic seizures. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic".

Pharmacological and neuroethological study of the acute and chronic effects of lamotrigine in the genetic audiogenic seizure hamster (GASH:Sal).

The present study aimed to investigate the behavioral and anticonvulsant effects of lamotrigine (LTG) on the genetic audiogenic seizure hamster (GASH:Sal), an animal model of audiogenic seizure that is in the validation process. To evaluate the efficiency of acute and chronic treatments with LTG, GASH:Sals were treated with LTG either acutely via intraperitoneal injection (5-20mg/kg) or chronically via oral administration (20-25mg/kg/day). Their behavior was assessed via neuroethological analysis, and the anticonvulsant effect of LTG was evaluated based on the appearance and the severity of seizures. The results showed that acute administration of LTG exerts an anticonvulsant effect at the lowest dose tested (5mg/kg) and that chronic oral LTG treatment exerts an anticonvulsant effect at a dose of 20-25mg/kg/day. Furthermore, LTG treatment induced a low rate of secondary adverse effects. This article is part of a Special Issue entitled "Genetic and Reflex Epilepsies, Audiogenic Seizures and Strains: From Experimental Models to the Clinic".

Speech rate in Parkinson's disease: A controlled study. / Estudio controlado del ritmo del habla en la enfermedad de Parkinson.

INTRODUCTION: Speech disturbances will affect most patients with Parkinson's disease (PD) over the course of the disease. The origin and severity of these symptoms are of clinical and diagnostic interest. PURPOSE: To evaluate the clinical pattern of speech impairment in PD patients and identify significant differences in speech rate and articulation compared to control subjects. Speech rate and articulation in a reading task were measured using an automatic analytical method. PATIENTS: A total of 39 PD patients in the 'on' state and 45 age-and sex-matched asymptomatic controls participated in the study. None of the patients experienced dyskinesias or motor fluctuations during the test. RESULTS: The patients with PD displayed a significant reduction in speech and articulation rates; there were no significant correlations between the studied speech parameters and patient characteristics such as L-dopa dose, duration of the disorder, age, and UPDRS III scores and Hoehn & Yahr scales. CONCLUSION: Patients with PD show a characteristic pattern of declining speech rate. These results suggest that in PD, disfluencies are the result of the movement disorder affecting the physiology of speech production systems.

REVISIÓN SISTEMÁTICA: ESTIMULACIÓN TRANSCRANEAL DE CORRIENTE DIRECTA EN MIGRAÑA CRÓNICA / SYSTEMATIC REVIEW: TRANSCRANIAL DIRECT CURRENT STIMULATION IN CHRONIC MIGRAINE / REVISÃO SISTEMÁTICA: ESTIMULAÇÃO TRANSCRANIAL DE TENSÃO DIRETA ATUAL NA ENXAQUECA CRÔNICA

La tDCS (Transcranial Direct-Current Stimulation), es una técnica no invasiva, indolora, segura y de bajo costo, capaz de modificar por medio de corrientes eléctricas directas la actividad de la corteza cerebral. El objetivo de esta revisión sistemática es describir la respuesta que se ha obtenido con el tratamiento de tDCS en pacientes con enfermedad de CM (Chronic Migraine). Método: Se efectuó una búsqueda de la bibliografía médica en las bases de datos Scielo, Springer y Pubmed. Se incluyeron las publicaciones donde se encontrara el termino -Estimulación Transcraneal con Corriente Directa- Migraña Crónica-. Se excluyeron investigaciones acerca de otras patologías, tratamientos implementados en CM con fármacos, Terapia de Electroshock, Estimulación Magnética Transcraneal y Estimulación Vagal. Resultados: De un total de 21 publicaciones consultadas, cumplieron los criterios de inclusión y exclusión para la presente revisión 3 referencias. Conclusiones: Los resultados de esta revisión sugieren que el uso de la tDCS es un método seguro que disminuye gradualmente la intensidad del dolor en los episodios de CM.

tDCS (Transcranial Direct-Current Stimulation) is a non-invasive, painless, safe and inexpensive technique, capable of changing through direct current electrical activity of the cerebral cortex. The objective of this systematic review is to describe the response obtained with tDCS treatment in patients with CM disease (Chronic Migraine). Method: A search of the medical literature in Scielo, Springer, and Pubmed data bases. Publications where the term - Transcranial Direct-Current Stimulation, Chronic Migraine was found were included. Research on other diseases, drug implemented in CM, Electroshock Therapy, Transcranial Magnetic Stimulation and Vagal stimulation treatments were excluded. Results: From a total of 21 publications, 3 references met the inclusion and exclusion criteria for this review. Conclusions: The results of this review suggest that the use of tDCS is a safe method that gradually decreases the intensity of pain episodes CM.

A TDCS (Transcranial Direct-Current Stimulation) é uma atividade corrente contínua não invasivo, indolor, segura e baixo custo, capaz de mudança através de tensão eléctrica direta a atividade córtex cerebral. O objetivo desta revisão sistemática é para descrever a resposta que foi obtida com o tratamento TDCS em pacientes com doença CM (Chronic Migraine). Método: A pesquisa da literatura médica nas bases de dados Scielo, Springer e Pubmed. Se incluíram Publicações onde se encontrou o termo -Estimulación Transcranial com corrente contínua enxaqueca Crônica. Foram excluídas investigações sobre outras doenças, tratamentos implementados em CM com medicamentos, a terapia de eletrochoque, Estimulação Magnética Transcraniana e estimulação vagal. Resultados: De um total de 21 publicações consultadas, preencheram os critérios de inclusão e exclusão para esta revisão 3 referências. Conclusões: Os resultados desta revisão sugerem que o uso da TDCS é um método seguro que, gradualmente, diminui a intensidade dos episódios de dor da CM.

Pharmacological and neuroethological studies of three antiepileptic drugs in the Genetic Audiogenic Seizure Hamster (GASH:Sal).

Epilepsy modeling is essential for understanding the basic mechanisms of the epileptic process. The Genetic Audiogenic Seizure Hamster (GASH:Sal) exhibits generalized tonic-clonic seizures of genetic origin in response to sound stimulation and is currently being validated as a reliable model of epilepsy. Here, we performed a pharmacological and neuroethological study using well-known and widely used antiepileptic drugs (AEDs), including phenobarbital (PB), valproic acid (VPA), and levetiracetam (LEV). The intraperitoneal administration of PB (5-20mg/kg) and VPA (100-300mg/kg) produced a dose-dependent decrease in GASH:Sal audiogenic seizure severity scores. The administration of LEV (30-100mg/kg) did not produce a clear effect. Phenobarbital showed a short plasmatic life and had a high antiepileptic effect starting at 10mg/kg that was accompanied by ataxia. Valproic acid acted only at high concentrations and was the AED with the most ataxic effects. Levetiracetam at all doses also produced sedation and ataxia side effects. We conclude that the GASH:Sal is a reliable genetic model of epilepsy suitable to evaluate AEDs.

Chronic administration of risperidone in a rat model of schizophrenia: a behavioural, morphological and molecular study.

In the present work we analyzed the effect of the chronic administration of risperidone (2mg/kg over 65 days) on behavioural, morphological and molecular aspects in an experimental model of schizophrenia obtained by bilateral injection of ibotenic acid into the ventral hippocampus of new-born rats. Our results show that during their adult lives the animals with hippocampal lesions exhibit different alterations, mainly at behavioural level and in the gene expression of dopamine D(2) and 5-HT(2A) receptors. However, at morphological level the study performed on the prefrontal cortex did not reveal any alterations in either the thickness or the number of cells immunoreactive for c-Fos, GFAP, CBP or PV. Overall, risperidone administration elicited a trend towards the recovery of the values previously altered by the hippocampal lesion, approaching the values seen in the animals without lesions. It may be concluded that the administration of risperidone in the schizophrenia model employed helps to improve the altered functions, with no significant negative effects.

Prepulse inhibition of the startle reflex in schizophrenia remains stable with short-term quetiapine.

PURPOSE: To study the short-term effect of treatment with quetiapine on prepulse inhibition (PPI) deficits of the startle reflex in schizophrenia patients. SUBJECTS AND METHODS: Using PPI, we studied a group of 21 schizophrenia patients and 16 controls. Seventeen of the patients were re-tested with PPI after 21 days of treatment with quetiapine. RESULTS: At baseline, an almost significant decrease in PPI was found in the patients as compared to the controls. PPI measurements did not change in the patients after 21 days of treatment with quetiapine, despite their clinical improvement. CONCLUSION: Our results suggest that short-term quetiapine treatment may not modify PPI measures in schizophrenia patients.

Chronic administration of risperidone to healthy rats: a behavioural and morphological study.

Taking into account that most of the experimental research into the effects of antipsychotic drugs has mainly focused on behavioural aspects, the aim of the present work is to investigate the effects of a chronic therapeutic dose of risperidone (1 mg/kg/day during 140 days) on both behavioural and morphological aspects in healthy rats. The behavioural results revealed only minor modifications in prepulse inhibition, showing the risperidone-treated group higher values at 70 days of treatment with respect to the vehicle group. Moreover, in the open-field test, this group showed a greater incidence of grooming. In the active avoidance test, no differences were found between the groups studied. Additionally, in the morphological study performed to analyse cortical thickness and the number of GFAP-, CaBP-, PV- and Fos-immunostained cells no differences were seen between the two groups studied. It is important to note that the risperidone-treated group showed a slight increase in the total number of cells counted, although this increase was not significant. Our results indicate that the chronic administration of therapeutic doses of risperidone does not produce any dramatic behavioural or morphological changes in healthy animals.

Correlation between prepulse inhibition and cortical perfusion during an attentional test in schizophrenia. A pilot study.

BACKGROUND: Processes underlying cortical hypoactivation in schizophrenia are poorly understood but some evidence suggests that a deficient sensory filtering is associated with the condition. This filtering deficit can be studied by using measures of prepulse inhibition (PPI) of the startle reflex. OBJECTIVE: To evaluate the contribution of sensory filtering deficits to cortical hypoperfusion during an attention test in schizophrenia. METHOD: Measurements of PPI of the startle reflex and perfusion during the performance of a Stroop test (assessed with single photon emission tomography) were obtained in 10 acutely treated schizophrenia patients (6 with recent onset, RO) and 16 control subjects. These measurements were compared between patients and controls and the correlation between PPI and perfusion was evaluated within each group, using Statistical Parametric Mapping. RESULTS: In comparison with normal subjects, the patients exhibited lower PPI, although the difference was not statistically significant. Perfusion was significantly lower in the prefrontal and premotor regions of the patients. In the patient group, a statistically significant difference was observed between PPI and perfusion in the parietal, premotor, and cingulate regions. When the associations were analyzed in the RO patients alone, a positive correlation was also found between prefrontal perfusion and PPI, while anterior hippocampal perfusion was inversely related to PPI. CONCLUSIONS: These results support the notion that deficient sensory-motor filtering is associated with decreased cortical task-related activation in schizophrenia.

Neurochemistry of the afferents to the rat cochlear root nucleus: possible synaptic modulation of the acoustic startle.

Afferents to the primary startle circuit are essential for the elicitation and modulation of the acoustic startle reflex (ASR). In the rat, cochlear root neurons (CRNs) comprise the first component of the acoustic startle circuit and play a crucial role in mediating the ASR. Nevertheless, the neurochemical pattern of their afferents remains unclear. To determine the distribution of excitatory and inhibitory inputs, we used confocal microscopy to analyze the immunostaining for vesicular glutamate and GABA transporter proteins (VGLUT1 and VGAT) on retrogradely labeled CRNs. We also used reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry to detect and localize specific neurotransmitter receptor subunits in the cochlear root. Our results show differential distributions of VGLUT1- and VGAT-immunoreactive endings around cell bodies and dendrites. The RT-PCR data showed a positive band for several ionotropic glutamate receptor subunits, M1-M5 muscarinic receptor subtypes, the glycine receptor alpha1 subunit (GlyRalpha1), GABAA, GABAB, and subunits of alpha2 and beta-noradrenergic receptors. By immunohistochemistry, we confirmed that CRN cell bodies exhibit positive immunoreaction for the glutamate receptor (GluR) 3 and NR1 GluR subunits. Cell bodies and dendrites were also positive for M2 and M4, and GlyRalpha1. Other subunits, such as GluR1 and GluR4 of the AMPA GluRs, were observed in glial cells neighboring unlabeled CRN cell bodies. We further confirmed the existence of noradrenergic afferents onto CRNs from the locus coeruleus by combining tyrosine hydroxylase immunohistochemistry and tract-tracing experiments. Our results provide valuable information toward understanding how CRNs might integrate excitatory and inhibitory inputs, and hence how they could elicit and modulate the ASR.

Electrophysiological responses of cochlear root neurons.

Cochlear root neurons (CRNs) are second-order neurons interspersed among the fibers of the cochlear nerve in certain rodents. They project, among other nuclei, mainly to the pontine reticular nucleus, and participate in the acoustic startle response (ASR), a short-latency motor reflex initiated by sudden intense sounds. The sound-evoked activity of CRNs has not previously been described. Here we describe extracellular responses of CRNs located in the infranuclear portion of the cochlear nerve root. CRNs exhibited secure responses to tone bursts, with first-spike latencies of approximately 2.2 ms. The characteristic frequencies of the recorded CRNs were about 30 kHz, and the best-characterized CRN had a threshold of 10 dB sound pressure level and sharpness of tuning similar to that of cochlear nerve fibers. The peristimulus time histograms were primary-like with notch. The observed response properties were consistent with the suggestion that CRNs provide the short-latency acoustic input to the reticular formation that leads to an ASR.

Study of the olivocochlear neurons using two different tracers, fast blue and cholera toxin, in hypothyroid rats.

Congenital hypothyroidism results in deafness that is caused by changes in the auditory receptor, including scanty development of the outer hair cells and a lack of synaptogenesis between these cells and the efferent system. although the afferent population is present. The normal efferent innervation of the cochlea originates in the superior olivary complex, arising from efferent neurons belonging to the lateral or to the medial olivocochlear system. In the rat, the former is constituted by neurons located in the lateral superior olivary nucleus, that project to the inner hair cells, while the later originates in the ventral nuclei of the trapezoid body and project to the outer hair cells. The aim of this work is to study the localization, number and morphology of the olivochochlear neurons in congenital hypothyroid animals by means of the injections of the retrograde tracers, either fast blue or cholera toxin, in the cochlea. The mean total number of labeled olivocochlear neurons after injection of fast blue in hypothyroid animals was 1,016, and in control ones was 1,027. Using cholera toxin, the mean total number of labeled olivocochlear neurons was slightly lower: 863 in hypothyroid animals versus 910 in control ones. Although both tracers showed no significant differences between groups, when the somatic area of the labeled olivocochlear neurons is considered, the size of all of the three different population of cells (lateral olivocochlear neurons, medial olivocochlear neurons and shell neurons) was significantly lower in the hypothyroid rats. This is the first study of the olivocochlear neurons in hypothyroid animals. The conclusion from this work is that in hypothyroid rats the labeled olivocochlear neurons are significantly smaller but that there is not any modification in the localization and number of the labeled olivocochlear neurons, suggesting that thyroid hormones are necessary for the neuronal growth. However, most of the medial olivocochlear neurons do not make contact with their target, so their maintenance suggests that the axons are in contact with other structures of the cochlea.

Projections of cochlear root neurons, sentinels of the rat auditory pathway.

In certain rodents, the root of the cochlear nerve contains a population of large neurons, known as cochlear root neurons (CRNs), an essential element of the primary acoustic startle pathway. To characterize the projections of the CRNs, we made stereotaxically guided, iontophoretic injections of biotinylated tracers into the cochlear nerve root of albino rats. CRN axons, which are remarkably thick, enter the trapezoid body, cross the midline, and ascend in the rostral aspect of the lateral lemniscus to reach the upper levels of the midbrain. As a group, CRN axons produce a characteristic pattern of profusely ramified collaterals that innervate specific brainstem regions. The main target of CRN axons is the contralateral pontine reticular formation, where collaterals terminate in the caudal pontine reticular nucleus (PnC) and, to a lesser degree, in the ventrolateral tegmental area, the oral pontine reticular nucleus, and the rostral and medial paralemniscal regions. Other targets of CRN axons include the lateral paragigantocellular nucleus of both sides, the ipsilateral facial motor nucleus and PnC, and the contralateral intercollicular tegmentum and superior colliculus. Notably, CRNs apparently do not innervate any of the nuclei of the auditory brainstem, as usually defined, even though their axons pass through or in close proximity to them. The fact that CRNs innervate several reticular and tectal structures that mediate auditory alerting and escape behaviors suggests that they are "early warning neurons," i.e., true sentinels of the auditory pathway.

[Hemochromatosis associated with hereditary spherocytosis]. / Asociación de hemocromatosis y esferocitosis hereditaria.

Hereditary spherocytosis is a chronic hemolytic anemia that very infrequently produces severe iron overload. Only 15 cases of hereditary spherocytosis associated with hemochromatosis have been described previously. It was initially thought that hemochromatosis was the result of the increase of iron stores secondary to chronic hemolysis. Afterwards, it became apparent that iron overload could appear in patients splenectomized. This fact suggested that spherocytosis and idiopathic hemochromatosis could be inherited independently. We describe the case of a 45-year-old man, with known hereditary spherocytosis, splenectomized at 5 years of age, who developed iron overload which affected his heart, liver and pancreas.

Asociacion de hemocromatosis y esferocitosis hereditaria / Association of hemochromatosis and hereditary spherocytosis

La esferocitosis hereditaria es una anemia hemolítica crónica que raramente presenta sobrecarga férrica. Sólo 15 casos de esferocitosis hereditaria y hemocromatosis fueron descriptos cpn anterioridad. Inicialmente, se había propuesto que la hemocromatosis era el resultado del depósito exagerado de hierro secundario a la hemólisis crónica y al aumento de la eritropoyesis. Se vió, con posterioridad, que la sobrecarga aparecía en sujetos esplenectomizados, sugiriendo este hecho la posibilidad de una herencia independiente de la esfrocitosis y de la hemacromatosis. Se presenta un paciente de 45 años, de sexo masculino, con el antecedente de esfocitosis hereditaria, esplenectomizado a los 5 años, que desarrolló sobrecarga de hierro con afección cardíaca, hepática y pancreática.

Asociacion de hemocromatosis y esferocitosis hereditaria / Association of hemochromatosis and hereditary spherocytosis

La esferocitosis hereditaria es una anemia hemolítica crónica que raramente presenta sobrecarga férrica. Sólo 15 casos de esferocitosis hereditaria y hemocromatosis fueron descriptos cpn anterioridad. Inicialmente, se había propuesto que la hemocromatosis era el resultado del depósito exagerado de hierro secundario a la hemólisis crónica y al aumento de la eritropoyesis. Se vió, con posterioridad, que la sobrecarga aparecía en sujetos esplenectomizados, sugiriendo este hecho la posibilidad de una herencia independiente de la esfrocitosis y de la hemacromatosis. Se presenta un paciente de 45 años, de sexo masculino, con el antecedente de esfocitosis hereditaria, esplenectomizado a los 5 años, que desarrolló sobrecarga de hierro con afección cardíaca, hepática y pancreática. (AU)