Publications by authors named "Luciene Covolan"

42 Publications

Adult brain activation in response to pain is changed by neonatal painful stimulation according to sex: A manganese-enhanced MRI study.

Eur J Neurosci 2021 01 9;53(2):571-587. Epub 2020 Sep 9.

Departamento de Fisiologia, Universidade Federal de São Paulo, São Paulo, Brazil.

Although it is known that nociceptive stimulation in the first postnatal week in rats is useful to model preterm pain, resulting in activation of specific brain areas, as assessed in vivo using manganese-enhanced magnetic resonance imaging (MEMRI), little is known about its long-term effects and sex specificity. Here we aimed to investigate whether inflammatory pain induced in male and female adult rats modify the pattern of brain activation between animals subjected or not to neonatal pain. For this, Complete Freund's adjuvant (CFA) was injected into the left hind paw of rat pups on postnatal day 1 (P1) or P8 to induce inflammatory response. During adulthood, CFA-treated and control animals were injected with CFA 1 hr prior MRI. MEMRI has the ability to enhance the contrast of selective brain structures in response to a specific stimulus, as the pain. MEMRI responses were consistent with activation of nociceptive pathways and these responses were reduced in animals treated with CFA on P1, but increased in animals treated on P8, mainly in the female group. In agreement, P8 female group showed exacerbated responses in the thermal nociceptive test. Using MEMRI, we conclude that the natural ability of adult rats to recognize and react to pain exposition is modified by neonatal painful exposition, mainly among females.
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http://dx.doi.org/10.1111/ejn.14948DOI Listing
January 2021

Chronic unpredictable restraint stress increases hippocampal pro-inflammatory cytokines and decreases motivated behavior in rats.

Stress 2020 07 14;23(4):427-436. Epub 2020 Jan 14.

Division of Neurosurgery, Harquail Centre for Neuromodulation, Sunnybrook Research Institute, University of Toronto, Toronto, Canada.

Most chronic stress protocols are too laborious or do not abide by the two main characteristics of the stress concept: uncontrollability and unpredictability. The goal of this study was to establish a simple and reliable model of chronic stress, while maintaining the main features of the concept. Animals were exposed to chronic movement restraint with variable duration (2, 4 or 6 h, in an unpredictable schedule) for 3 weeks and assessed in several physiological and behavioral readouts known to reflect chronic stress states. Body weight, levels of plasma corticosterone, hippocampal pro-and anti-inflammatory cytokines, anxiety-like (novelty suppressed feeding and elevated plus maze) and motivated behaviors (sucrose negative contrast test and forced swim test) were evaluated three days after the end of the chronic protocol. Stressed animals had a lower body weight gain, higher levels of cytokines in the hippocampus, reduced suppression of a low concentration sucrose solution and increased immobility in the forced swim test. Based on these data, we suggest that chronic movement restraint with variable duration may be a suitable and simple protocol for the study of changes induced by chronic stress and for the testing of possible treatments relevant to psychiatry.
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http://dx.doi.org/10.1080/10253890.2020.1712355DOI Listing
July 2020

The neural response to deep brain stimulation of the anterior nucleus of the thalamus: A MEMRI and c-Fos study.

Brain Res Bull 2019 04 15;147:133-139. Epub 2019 Jan 15.

Department of Physiology, Universidade Federal de Sao Paulo, Sao Paulo, Brazil; Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address:

Background: Deep brain stimulation (DBS) refers to the delivery of electric current to specific deep brain structures through implanted electrodes. Recently approved for use in United States, DBS to the anterior nucleus of thalamus (ANT) is a safe and effective alternative treatment for medically refractory seizures. Despite the anti-seizure effects of ANT DBS, preclinical and clinical studies have failed to demonstrate it actions at a whole brain level.

Objective: Here, we used a magnetic resonance imaging (MRI)-based approach in healthy adult rats to investigate the effects of ANT DBS through the circuit of Papez, which has central role in the generation and propagation of limbic seizures, in temporal lobe epilepsy (TLE).

Methods: After ANT electrode implantation and recovery, ANT DBS and SHAM (sham animals had electrodes implanted but were not stimulated) rats received one single injection of the contrast enhancer, manganese chloride (60 mg/kg, ip). Twelve hours after, rats underwent the baseline scan using the MEMRI (Manganese-Enhanced Magnetic Resonance Imaging) technique. We used the same MEMRI and parvalbumin sequence to follow the DBS delivered during 1 h (130 Hz and 200 μA). Perfusion was followed by subsequent c-Fos and parvalbumin immunostaining of brain sections.

Results: Acute unilateral ANT DBS significantly reduced the overall manganese uptake and consequently, the MEMRI contrast in the circuit of Papez. Additionally, c-Fos expression was bilaterally increased in the cingulate cortex and posterior hypothalamus, areas directly connected to ANT, as well as in amygdala and subiculum, within the limbic circuitry.

Conclusion: Our data indicate that MEMRI can be used to detect whole-brain responses to DBS, as the high frequency stimulation parameters used here caused a significant reduction of cell activity in the circuit of Papez that might help to explain the antiepileptic effects of ANT DBS.
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http://dx.doi.org/10.1016/j.brainresbull.2019.01.011DOI Listing
April 2019

Is Mossy Fiber Sprouting a Potential Therapeutic Target for Epilepsy?

Front Neurol 2018 30;9:1023. Epub 2018 Nov 30.

Department of Physiology, Universidade Federal de São Paulo, São Paulo, Brazil.

Mesial temporal lobe epilepsy (MTLE) caused by hippocampal sclerosis is one of the most frequent focal epilepsies in adults. It is characterized by focal seizures that begin in the hippocampus, sometimes spread to the insulo-perisylvian regions and may progress to secondary generalized seizures. Morphological alterations in hippocampal sclerosis are well defined. Among them, hippocampal sclerosis is characterized by prominent cell loss in the hilus and CA1, and abnormal mossy fiber sprouting (granular cell axons) into the dentate gyrus inner molecular layer. In this review, we highlight the role of mossy fiber sprouting in seizure generation and hippocampal excitability and discuss the response of alternative treatment strategies in terms of MFS and spontaneous recurrent seizures in models of TLE (temporal lobe epilepsy).
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http://dx.doi.org/10.3389/fneur.2018.01023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6284045PMC
November 2018

A brief history of salivary gland surgery.

Rev Col Bras Cir 2017 Jul-Aug;44(4):403-412

UNIFESP, Centro de Desenvolvimento de Modelos Experimentais (CEDEME), São Paulo, SP, Brasil.

Salivary gland neoplasms are a relatively uncommon disease, with nearly one case per 100.000 adults estimated per year and an overall incidence of 1% of all neoplasms. The benign neoplasms are majority and the prognosis depends on the histologic type, grade, localization, soft tissue infiltration, regional and distant metastasis. The main treatment is surgery with caution to facial nerve in the major salivary glands, followed by radiotherapy and chemotherapy in selected cases. The objective of this review is to provide the lector an historic approach about salivary gland diseases treatment, with special attention to the parotid neoplasms and its peculiarities associated to those who studied these glands in their history course.
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http://dx.doi.org/10.1590/0100-69912017004004DOI Listing
July 2018

Long-Term Effects of Anterior Thalamic Nucleus Deep Brain Stimulation on Spatial Learning in the Pilocarpine Model of Temporal Lobe Epilepsy.

Neuromodulation 2018 Feb 28;21(2):160-167. Epub 2017 Sep 28.

Department of de Physiology, Universidade Federal de São Paulo, São Paulo, Sao Paulo, Brazil.

Introduction And Objectives: Cognitive impairment is a significant comorbidity of temporal lobe epilepsy that is associated with extensive hippocampal cell loss. Deep brain stimulation (DBS) of the anterior thalamic nucleus (ANT) has been used for the treatment of refractory partial seizures. In the pilocarpine model of epilepsy, ANT DBS applied during status epilepticus (SE) reduces hippocampal inflammation and apoptosis. When given to chronic epileptic animals it reduces hippocampal excitability and seizure frequency. Here, we tested whether ANT DBS delivered during SE and the silent phase of the pilocarpine model would reduce cognitive impairment when animals became chronically epileptic.

Materials And Methods: SE was induced by a systemic pilocarpine injection (320 mg/kg). Immediately after SE onset, rats were assigned to receive DBS during the first six hours of SE (n = 8; DBSa group) or during SE + the silent period (i.e., 6 h/day until the animals developed the first spontaneous recurrent seizure; n = 10; DBSs group). Four months following SE, animals underwent water maze testing and histological evaluation. Nonstimulated chronic epileptic animals (n = 13; PCTL group) and age-matched naïve rats (n = 11, CTL group) were used as controls. Results were analyzed by repeated-measures analyses of variance (RM_ANOVA) and one-way ANOVAs, followed by Newman-Keuls post hoc tests.

Results: Although all groups learned the spatial task, epileptic animals with or without DBS spent significantly less time in the platform quadrant, denoting a spatial memory deficit (p < 0.02). Despite these negative behavioral results, we found that animals given DBS had a significantly higher number of cells in the CA1 region and dentate gyrus. Mossy fiber sprouting was similar among all epileptic groups.

Conclusions: Despite lesser hippocampal neuronal loss, ANT DBS delivered either during SE or during SE and the silent phase of the pilocarpine model did not mitigate memory deficits in chronic epileptic rats.
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http://dx.doi.org/10.1111/ner.12688DOI Listing
February 2018

Transplantation of inhibitory precursor cells from medial ganglionic eminence produces distinct responses in two different models of acute seizure induction.

Epilepsy Behav 2017 05 17;70(Pt A):125-130. Epub 2017 Apr 17.

Laboratório de Neurofisiologia, Universidade Federal de São Paulo - UNIFESP, São Paulo, Brazil. Electronic address:

Medial ganglionic eminence (MGE) is one of the sources of inhibitory interneurons during development. Following transplantation in postnatal developing brain, MGE cells can increase local inhibition suggesting a possible protection to GABAergic dysfunction in brain disorders, such as epilepsy. Since it has been shown that MGE-derived cells harvested as neurospheres are able to suppress seizures, it might be important to investigate whether these protective effects would change in different seizure models. Here, we used pentylenetetrazole-(PTZ) and maximal electroshock (MES)-induced seizure models to test whether the transplantation of MGE cells would increase the threshold to trigger acute seizures. When transplanted into the neocortex (layers 3-4) of neonatal mice (postnatal days 3-4), MGE cells were able to survive and were mainly found in piriform cortex, fimbria, and ventricular wall regions. Additionally, the number of GFP+ cells found in the brains of mice induced with PTZ and MES differed significantly and suggests proliferation and larger survival rate of MGE-transplanted cells after PTZ, but not MES-induced seizures. Following transplantation, there was a reduction in the number of animals presenting mild and severe seizures induced by PTZ. Furthermore, MGE-cell transplantation was able to increase threshold to seizures induced by PTZ, but was not able to prevent seizure spread induced by MES.
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http://dx.doi.org/10.1016/j.yebeh.2017.03.015DOI Listing
May 2017

Effects of GABAa receptor antagonists on motor behavior in pharmacological Parkinson's disease model in mice.

Physiol Rep 2017 Mar;5(6)

Laboratory of Biophysiopharmacology, Universidade Federal de Mato Grosso do Sul, Campo Grande, Brazil.

The aim of this study was to evaluate the effects of two gamma-amino butyric acid (GABA)a receptor antagonists on motor behavioral tasks in a pharmacological model of Parkinson disease (PD) in rodents. Ninety-six Swiss mice received intraperitoneal injection of Haloperidol (1 mg/kg) to block dopaminergic receptors. GABAa receptors antagonists Bicuculline (1 and 5 mg/kg) and Flumazenil (3 and 6 mg/kg) were used for the assessment of the interaction among these neurotransmitters, in this PD model. The motor behavior of the animals was evaluated in the catalepsy test (30, 60, and 90 min after drugs application), through open field test (after 60 min) and trough functional gait assessment (after 60 min). Both Bicuculline and Flumazenil were able to partially reverse catalepsy induced by Haloperidol. In the open field test, Haloperidol reduced the number of horizontal and vertical exploration of the animals, which was not reversed trough application of GABAa antagonists. Furthermore, the functional gait assessment was not sensitive enough to detect motor changes in this animal model of PD. There is an interaction between dopamine and GABA in the basal ganglia and the blocking GABAa receptors may have therapeutic potential in the treatment of PD.
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http://dx.doi.org/10.14814/phy2.13081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371543PMC
March 2017

Effects of A1 receptor agonist/antagonist on spontaneous seizures in pilocarpine-induced epileptic rats.

Epilepsy Behav 2016 08 29;61:168-173. Epub 2016 Jun 29.

Disciplina de Neurofisiologia, Universidade Federal de São Paulo, São Paulo, Brazil. Electronic address:

Adenosine is an endogenous anticonvulsant that activates pre- and postsynaptic adenosine A1 receptors. A1 receptor agonists increase the latency for the development of seizures and status epilepticus following pilocarpine administration. Although hippocampal adenosine is increased in the chronic phase of the pilocarpine model, it is not known whether the modulation of A1 receptors may influence the frequency of spontaneous recurrent seizures (SRS). Here, we tested the hypothesis that the A1 receptor agonist RPia ([R]-N-phenylisopropyladenosine) and the A1 antagonist DPCPX (8-Cyclopentyl-1,3-dipropylxanthine) administered to chronic pilocarpine epileptic rats would respectively decrease and increase the frequency of SRS and hippocampal excitability. Four months after Pilo-induced SE, chronic epileptic rats were video-monitored for the recording of SRS before (basal) and after a 2-week treatment with RPia (25μg/kg) or DPCPX (50μg/kg). Following sacrifice, brain slices were studied with electrophysiology. We found that rats given RPia had a 93% nonsignificant reduction in the frequency of seizures compared with their own pretreatment baseline. In contrast, the administration of DPCPX resulted in an 87% significant increase in seizure rate. Nontreated epileptic rats had a similar frequency of seizures along the study. Corroborating our behavioral data, in vitro recordings showed that slices from animals previously given DPCPX had a shorter latency to develop epileptiform activity, longer and higher DC shifts, and higher spike amplitude compared with slices from nontreated Pilo controls. In contrast, smaller spike amplitude was recorded in slices from animals given RPia. In summary, the administration of A1 agonists reduced hippocampal excitability but not the frequency of spontaneous recurrent seizures in chronic epileptic rats, whereas A1 receptor antagonists increased both.
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http://dx.doi.org/10.1016/j.yebeh.2016.05.036DOI Listing
August 2016

Characterization of Intracranial Pressure Behavior in Chronic Epileptic Animals: A Preliminary Study.

Acta Neurochir Suppl 2016 ;122:329-33

Physics Institute of Sao Carlos, University of Sao Paulo, Sao Carlos, Brazil.

Intracranial pressure (ICP) is a major neurological parameter in animals and humans. ICP is a function of the relationship between the contents of the cranium (brain parenchyma, cerebrospinal fluid, and blood) and the volume of the skull. Increased ICP can cause serious physiological effects or even death in patients who do not quickly receive proper care, which includes ICP monitoring. Epilepsies are a set of central nervous system disorders resulting from abnormal and excessive neuronal discharges, usually associated with hypersynchronism and/or hyperexcitability. Temporal lobe epilepsy (TLE) is one of the most common forms of epilepsy and is also refractory to medication. ICP characteristics of subjects with epilepsy have not been elucidated because there are few studies associating these two important neurological factors. In this work, an invasive (ICPi) and the new minimally invasive (ICPmi) methods were used to evaluate ICP features in rats with chronic epilepsy, induced by the experimental model of pilocarpine, capable of generating the main features of human TLE in these animals.
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http://dx.doi.org/10.1007/978-3-319-22533-3_65DOI Listing
July 2017

Effects of Sulpiride on True and False Memories of Thematically Related Pictures and Associated Words in Healthy Volunteers.

Front Psychiatry 2016 18;7:28. Epub 2016 Mar 18.

Department of Psychobiology, Universidade Federal de São Paulo , São Paulo , Brazil.

Episodic memory, working memory, emotional memory, and attention are subject to dopaminergic modulation. However, the potential role of dopamine on the generation of false memories is unknown. This study defined the role of the dopamine D2 receptor on true and false recognition memories. Twenty-four young, healthy volunteers ingested a single dose of placebo or 400 mg oral sulpiride, a dopamine D2-receptor antagonist, just before starting the recognition memory task in a randomized, double-blind, and placebo-controlled trial. The sulpiride group presented more false recognitions during visual and verbal processing than the placebo group, although both groups had the same indices of true memory. These findings demonstrate that dopamine D2 receptors blockade in healthy volunteers can specifically increase the rate of false recognitions. The findings fit well the two-process view of causes of false memories, the activation/monitoring failures model.
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http://dx.doi.org/10.3389/fpsyt.2016.00028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4796014PMC
April 2016

Facial nerve identification with fluorescent dye in rats.

Acta Cir Bras 2016 Feb;31(2):92-102

Otorhinolaryngology Head and Neck Surgery Department, UNIFESP, Sao Paulo, SP, Brazil.

PURPOSE The parotidectomy technique still has an elevated paresis and paralysis index, lowering patient life's quality. The correct identification of the facial nerve can prevent nerve damage. Fluorescent dye identifies nerves in experimental studies but only few articles focused its use on facial nerve study in parotidectomies. We aimed to stain the rat facial nerve with fluorescent dye to facilitate visualization and dissection in order to prevent injuries. METHODS Forty adult male Wistar rats were submitted to facial injection of saline solution (Gsf-control group, 10) or fluorescent dye solution (Gdye group, 30) followed by parotidectomy preserving the facial nerve, measuring the time for localization and facility of localization (LocTime and LFN). Nerve function was assessed using the Vibrissae Movements (PMV) and Eyelid Closure Motion (PFP) scores. RESULTS Nerve localization was faster in Gdye group, with 83% Easy LFN rate. The Gdye group presented with low nerve injury degree and better PMV and PFP scores, with high sensitivity and accuracy. CONCLUSIONS This experimental method of facial nerve fluorescence was effective for intraoperative nerve visualization, identification and preservation. The technique may be used in future facial nerve studies, translated to humans, contributing to the optimization of parotid surgery in the near future.
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http://dx.doi.org/10.1590/S0102-865020160020000003DOI Listing
February 2016

Replacement of Asymmetric Synaptic Profiles in the Molecular Layer of Dentate Gyrus Following Cycloheximide in the Pilocarpine Model in Rats.

Front Psychiatry 2015 17;6:157. Epub 2015 Nov 17.

Department of Physiology, Universidade Federal de São Paulo , São Paulo , Brazil.

Mossy fiber sprouting is among the best-studied forms of post-lesional synaptic plasticity and is regarded by many as contributory to seizures in both humans and animal models of epilepsy. It is not known whether mossy fiber sprouting increases the number of synapses in the molecular layer or merely replaces lost contacts. Using the pilocarpine (Pilo) model of status epilepticus to induce mossy fiber sprouting, and cycloheximide (CHX) to block this sprouting, we evaluated at the ultrastructural level the number and type of asymmetric synaptic contacts in the molecular layer of the dentate gyrus. As expected, whereas Pilo-treated rats had dense silver grain deposits in the inner molecular layer (IML) (reflecting mossy fiber sprouting), pilocarpine + cycloheximide (CHX + Pilo)-treated animals did not differ from controls. Both groups of treated rats (Pilo group and CHX + Pilo group) had reduced density of asymmetric synaptic profiles (putative excitatory synaptic contacts), which was greater for CHX-treated animals. For both treated groups, the loss of excitatory synaptic contacts was even greater in the outer molecular layer than in the best-studied IML (in which mossy fiber sprouting occurs). These results indicate that mossy fiber sprouting tends to replace lost synaptic contacts rather than increase the absolute number of contacts. We speculate that the overall result is more consistent with restored rather than with increased excitability.
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http://dx.doi.org/10.3389/fpsyt.2015.00157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4647073PMC
December 2015

Impact of neonatal anoxia on adult rat hippocampal volume, neurogenesis and behavior.

Behav Brain Res 2016 Jan 28;296:331-338. Epub 2015 Sep 28.

Departamento de Anatomia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.

Neonates that suffer oxygen deprivation during birth can have long lasting cognitive deficits, such as memory and learning impairments. Hippocampus, one of the main structures that participate in memory and learning processes, is a plastic and dynamic structure that conserves during life span the property of generating new cells which can become neurons, the so-called neurogenesis. The present study investigated whether a model of rat neonatal anoxia, that causes only respiratory distress, is able to alter the hippocampal volume, the neurogenesis rate and has functional implications in adult life. MRI analysis revealed significant hippocampal volume decrease in adult rats who had experienced neonatal anoxia compared to control animals for rostral, caudal and total hippocampus. In addition, these animals also had 55.7% decrease of double-labelled cells to BrdU and NeuN, reflecting a decrease in neurogenesis rate. Finally, behavioral analysis indicated that neonatal anoxia resulted in disruption of spatial working memory, similar to human condition, accompanied by an anxiogenic effect. The observed behavioral alterations caused by oxygen deprivation at birth might represent an outcome of the decreased hippocampal neurogenesis and volume, evidenced by immunohistochemistry and MRI analysis. Therefore, based on current findings we propose this model as suitable to explore new therapeutic approaches.
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http://dx.doi.org/10.1016/j.bbr.2015.08.039DOI Listing
January 2016

Early postnatal nociceptive stimulation results in deficits of spatial memory in male rats.

Neurobiol Learn Mem 2015 Nov 5;125:120-5. Epub 2015 Sep 5.

Departamento de Fisiologia, Universidade Federal de São Paulo, São Paulo 04023-062, Brazil. Electronic address:

Prematurely-born infants are exposed to multiple invasive procedures while in the intensive care unit. Newborn rats and humans have similar behavioral responses to noxious stimulation. Previous studies have shown that early noxious stimuli may alter dentate gyrus neurogenesis and the behavioral repertoire of adult rats. We evaluated the late effects of noxious stimulation administered during different phases of development on two spatial memory tests; object recognition (OR) and Morris water maze (WM) tests. Noxious stimulation was induced by an intra-plantar injection of complete Freund's adjuvant (CFA) on postnatal (P) day 1 (group P1) or 8 (P8). Control animals were not stimulated. Behavioral tests were conducted on P60 in both male and female animals. In the WM, three domains were evaluated: acquisition, probe trial performance and reversal re-acquisition. The number of Nissl stained cells in the dentate granule cell layer was assessed by stereological counting. The OR test revealed that P1 male rats had poor long-term memory compared to the control and P8 groups. In the WM, no short- or long-term memory differences were detected between early postnatal-stimulated male and female rats and their respective controls. However, the ability to find the hidden platform in a new position was reduced in P1 male rats. The number of dentate granule cells in P8 males was higher than in all other groups. This study demonstrates that noxious stimulation on P1 results in spatial learning deficits in male animals, but does not disrupt the development of the hippocampus-dependent strategies of learning and memory.
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http://dx.doi.org/10.1016/j.nlm.2015.08.012DOI Listing
November 2015

Deep brain stimulation induces antiapoptotic and anti-inflammatory effects in epileptic rats.

J Neuroinflammation 2015 Sep 4;12:162. Epub 2015 Sep 4.

Behavioural Neurobiology Laboratory, Centre for Addiction and Mental Health, Toronto, Canada.

Background: Status epilepticus (SE) is a severe condition that may lead to hippocampal cell loss and epileptogenesis. Some of the mechanisms associated with SE-induced cell death are excitotoxicity, neuroinflammation, and apoptosis.

Objective: The objective of the present study is to test the hypothesis that DBS has anti-inflammatory and antiapoptotic effects when applied during SE.

Methods: Rats undergoing pilocarpine-induced SE were treated with anterior thalamic nucleus (AN) deep brain stimulation (DBS). Inflammatory changes and caspase 3 activity were measured within 1 week of treatment.

Results: In pilocarpine-treated rats, DBS countered the significant increase in hippocampal caspase 3 activity and interleukin-6 (IL-6) levels that follows SE but had no effect on tumor necrosis factor α (TNFα).

Conclusions: DBS has anti-inflammatory and antiapoptotic effects when given to animals undergoing status.
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http://dx.doi.org/10.1186/s12974-015-0384-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558969PMC
September 2015

pH during non-synaptic epileptiform activity-computational simulations.

Phys Biol 2015 Sep 2;12(5):056007. Epub 2015 Sep 2.

Laboratório de Neurociência Experimental e Computacional, Departamento de Engenharia de Biossistemas, Universidade Federal de São João del-Rei (UFSJ), Brazil.

The excitability of neuronal networks is strongly modulated by changes in pH. The origin of these changes, however, is still under debate. The high complexity of neural systems justifies the use of computational simulation to investigate mechanisms that are possibly involved. Simulated neuronal activity includes non-synaptic epileptiform events (NEA) induced in hippocampal slices perfused with high-K(+) and zero-Ca(2+), therefore in the absence of the synaptic circuitry. A network of functional units composes the NEA model. Each functional unit represents one interface of neuronal/extracellular space/glial segments. Each interface contains transmembrane ionic transports, such as ionic channels, cotransporters, exchangers and pumps. Neuronal interconnections are mediated by gap-junctions, electric field effects and extracellular ionic fluctuations modulated by extracellular electrodiffusion. Mechanisms investigated are those that change intracellular and extracellular ionic concentrations and are able to affect [H(+)]. Our simulations suggest that the intense fluctuations in intra and extracellular concentrations of Na(+), K(+) and Cl(-) that accompany NEA are able to affect the combined action of the Na(+)/H(+) exchanger (NHE), [HCO(-)(3)]/Cl(-) exchanger (HCE), H(+) pump and the catalytic activity of intra and extracellular carbonic anhydrase. Cellular volume changes and extracellular electrodiffusion are responsible for modulating pH.
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http://dx.doi.org/10.1088/1478-3975/12/5/056007DOI Listing
September 2015

Manganese-Enhanced MRI: Biological Applications in Neuroscience.

Front Neurol 2015 10;6:161. Epub 2015 Jul 10.

Department of Physiology, Universidade Federal de São Paulo - UNIFESP , São Paulo , Brazil.

Magnetic resonance imaging (MRI) is an excellent non-invasive tool to investigate biological systems. The administration of the paramagnetic divalent ion manganese (Mn(2+)) enhances MRI contrast in vivo. Due to similarities between Mn(2+) and calcium (Ca(2+)), the premise of manganese-enhanced MRI (MEMRI) is that the former may enter neurons and other excitable cells through voltage-gated Ca(2+) channels. As such, MEMRI has been used to trace neuronal pathways, define morphological boundaries, and study connectivity in morphological and functional imaging studies. In this article, we provide a brief overview of MEMRI and discuss recently published data to illustrate the usefulness of this method, particularly in animal models.
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http://dx.doi.org/10.3389/fneur.2015.00161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498388PMC
July 2015

Expression of aquaporin 2 following facial nerve crush in rats.

Acta Otolaryngol 2015 Jul 11;135(7):741-5. Epub 2015 Mar 11.

Department of Otorhinolaryngology.

Conclusion: We demonstrated an early increase in aquaporin 2 (AQP2) expression in a motor nerve (extratemporal facial nerve, FN) following acute peripheral compression (crush), concomitant to effective development of motor dysfunction (facial palsy). The early increase in AQP2 expression that occurred concomitantly with the appearance of a deficit in a peripheral motor nerve suggests that this protein is involved in the physiological events associated with post-injury edema, similar to the already demonstrated behavior of AQP4 in the central nervous system (CNS).

Objective: The aim of this study was to assess the expression of AQP2 in the FN of rats up to 7 days after crush.

Methods: The extratemporal trunk of the right FN of rats was subjected to mechanical crush, and the expression of AQP2 in the affected (right) and non-affected (left) FN was measured by means of western blotting at days 1, 3, and 7 after injury. Behavioral analysis of the development of facial palsy was also performed over the same time period.

Results: Increased expression of AQP2 was shown in the affected FN compared with its corresponding control at day 1 after compression, simultaneously with the appearance of facial palsy.
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http://dx.doi.org/10.3109/00016489.2015.1010104DOI Listing
July 2015

Role of adenosine in the antiepileptic effects of deep brain stimulation.

Front Cell Neurosci 2014 2;8:312. Epub 2014 Oct 2.

Disciplina de Neurofisiologia, Universidade Federal de São Paulo São Paulo, Brazil.

Despite the effectiveness of anterior thalamic nucleus (AN) deep brain stimulation (DBS) for the treatment of epilepsy, mechanisms responsible for the antiepileptic effects of this therapy remain elusive. As adenosine modulates neuronal excitability and seizure activity in animal models, we hypothesized that this nucleoside could be one of the substrates involved in the effects of AN DBS. We applied 5 days of stimulation to rats rendered chronically epileptic by pilocarpine injections and recorded epileptiform activity in hippocampal slices. We found that slices from animals given DBS had reduced hippocampal excitability and were less susceptible to develop ictal activity. In live animals, AN DBS significantly increased adenosine levels in the hippocampus as measured by microdialysis. The reduced excitability of DBS in vitro was completely abolished in animals pre-treated with A1 receptor antagonists and was strongly potentiated by A1 receptor agonists. We conclude that some of the antiepileptic effects of DBS may be mediated by adenosine.
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http://dx.doi.org/10.3389/fncel.2014.00312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4183090PMC
October 2014

Glutamate reduces glucose utilization while concomitantly enhancing AQP9 and MCT2 expression in cultured rat hippocampal neurons.

Front Neurosci 2014 12;8:246. Epub 2014 Aug 12.

Laboratory of Neuroenergetics, Department of Physiology, University of Lausanne Lausanne, Switzerland.

The excitatory neurotransmitter glutamate has been reported to have a major impact on brain energy metabolism. Using primary cultures of rat hippocampal neurons, we observed that glutamate reduces glucose utilization in this cell type, suggesting alteration in mitochondrial oxidative metabolism. The aquaglyceroporin AQP9 and the monocarboxylate transporter MCT2, two transporters for oxidative energy substrates, appear to be present in mitochondria of these neurons. Moreover, they not only co-localize but they interact with each other as they were found to co-immunoprecipitate from hippocampal neuron homogenates. Exposure of cultured hippocampal neurons to glutamate 100 μM for 1 h led to enhanced expression of both AQP9 and MCT2 at the protein level without any significant change at the mRNA level. In parallel, a similar increase in the protein expression of LDHA was evidenced without an effect on the mRNA level. These data suggest that glutamate exerts an influence on neuronal energy metabolism likely through a regulation of the expression of some key mitochondrial proteins.
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http://dx.doi.org/10.3389/fnins.2014.00246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4130107PMC
August 2014

Deep brain stimulation in rats: different targets induce similar antidepressant-like effects but influence different circuits.

Neurobiol Dis 2014 Nov 13;71:205-14. Epub 2014 Aug 13.

Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada.

Recent studies in patients with treatment-resistant depression have shown similar results with the use of deep brain stimulation (DBS) in the subcallosal cingulate gyrus (SCG), ventral capsule/ventral striatum (VC/VS) and nucleus accumbens (Acb). As these brain regions are interconnected, one hypothesis is that by stimulating these targets one would just be influencing different relays in the same circuitry. We investigate behavioral, immediate early gene expression, and functional connectivity changes in rats given DBS in homologous regions, namely the ventromedial prefrontal cortex (vmPFC), white matter fibers of the frontal region (WMF) and nucleus accumbens. We found that DBS delivered to the vmPFC, Acb but not WMF induced significant antidepressant-like effects in the FST (31%, 44%, and 17% reduction in immobility compared to controls). Despite these findings, stimulation applied to these three targets induced distinct patterns of regional activity and functional connectivity. While animals given vmPFC DBS had increased cortical zif268 expression, changes after Acb stimulation were primarily observed in subcortical structures. In animals receiving WMF DBS, both cortical and subcortical structures at a distance from the target were influenced by stimulation. In regard to functional connectivity, DBS in all targets decreased intercorrelations among cortical areas. This is in contrast to the clear differences observed in subcortical connectivity, which was reduced after vmPFC DBS but increased in rats receiving Acb or WMF stimulation. In conclusion, results from our study suggest that, despite similar antidepressant-like effects, stimulation of the vmPFC, WMF and Acb induces distinct changes in regional brain activity and functional connectivity.
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http://dx.doi.org/10.1016/j.nbd.2014.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756089PMC
November 2014

Cortical modulation of pain: comments on "exacerbation of tonic but not phasic pain by entorhinal cortex lesions".

Neurosci Lett 2014 Oct 13;581:135-6. Epub 2014 Aug 13.

Departmento of Phyisiology, Universidade Federal de São Paulo - UNIFESP, São Paulo 04023-062, Brazil. Electronic address:

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http://dx.doi.org/10.1016/j.neulet.2014.08.013DOI Listing
October 2014

Changes in Hippocampal Volume are Correlated with Cell Loss but Not with Seizure Frequency in Two Chronic Models of Temporal Lobe Epilepsy.

Front Neurol 2014 1;5:111. Epub 2014 Jul 1.

Departamento de Fisiologia, Universidade Federal de São Paulo - UNIFESP , São Paulo , Brazil.

Kainic acid (KA) or pilocarpine (PILO) have been used in rats to model human temporal lobe epilepsy (TLE) but the distribution and severity of structural lesions between these two models may differ. Magnetic resonance imaging (MRI) studies have used quantitative measurements of hippocampal T2 (T2HP) relaxation time and volume, but simultaneous comparative results have not been reported yet. The aim of this study was to compare the MRI T2HP and volume with histological data and frequency of seizures in both models. KA- and PILO-treated rats were imaged with a 2 T MRI scanner. T2HP and volume values were correlated with the number of cells, mossy fiber sprouting, and spontaneous recurrent seizures (SRS) frequency over the 9 months following status epilepticus (SE). Compared to controls, KA-treated rats had unaltered T2HP, pronounced reduction in hippocampal volume and concomitant cell reduction in granule cell layer, CA1 and CA3 at 3 months post SE. In contrast, hippocampal volume was unchanged in PILO-treated animals despite detectable increased T2HP and cell loss in granule cell layer, CA1 and CA3. In the following 6 months, MRI hippocampal volume remained stable with increase of T2HP signal in the KA-treated group. The number of CA1 and CA3 cells was smaller than age-matched CTL group. In contrast, PILO group had MRI volumetric reduction accompanied by reduction in the number of CA1 and CA3 cells. In this group, T2HP signal was unaltered at 6 or 9 months after status. Reductions in the number of cells were not progressive in both models. Notably, the SRS frequency was higher in PILO than in the KA model. The volumetry data correlated well with tissue damage in the epileptic brain, suggesting that MRI may be useful for tracking longitudinal hippocampal changes, allowing the assessment of individual variability and disease progression. Our results indicate that the temporal changes in hippocampal morphology are distinct for both models of TLE and that these are not significantly correlated to the frequency of SRS.
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http://dx.doi.org/10.3389/fneur.2014.00111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4076745PMC
July 2014

Effects of anterior thalamic nucleus deep brain stimulation in chronic epileptic rats.

PLoS One 2014 3;9(6):e97618. Epub 2014 Jun 3.

Disciplina de Neurofisiologia, Universidade Federal de São Paulo, São Paulo, Brazil; Behavioural Neurobiology Laboratory, Centre for Addiction and Mental Health, Toronto, Canada; Division of Neurosurgery, Toronto Western Hospital, University of Toronto, Toronto, Canada.

Deep brain stimulation (DBS) has been investigated for the treatment of epilepsy. In rodents, an increase in the latency for the development of seizures and status epilepticus (SE) has been reported in different animal models but the consequences of delivering stimulation to chronic epileptic animals have not been extensively addressed. We study the effects of anterior thalamic nucleus (AN) stimulation at different current intensities in rats rendered epileptic following pilocarpine (Pilo) administration. Four months after Pilo-induced SE, chronic epileptic rats were bilaterally implanted with AN electrodes or had sham-surgery. Stimulation was delivered for 6 h/day, 5 days/week at 130 Hz, 90 µsec. and either 100 µA or 500 µA. The frequency of spontaneous recurrent seizures in animals receiving stimulation was compared to that recorded in the preoperative period and in rats given sham treatment. To investigate the effects of DBS on hippocampal excitability, brain slices from animals receiving AN DBS or sham surgery were studied with electrophysiology. We found that rats treated with AN DBS at 100 µA had a 52% non-significant reduction in the frequency of seizures as compared to sham-treated controls and 61% less seizures than at baseline. Animals given DBS at 500 µA had 5.1 times more seizures than controls and a 2.8 fold increase in seizure rate as compared to preoperative values. In non-stimulated controls, the average frequency of seizures before and after surgery remained unaltered. In vitro recordings have shown that slices from animals previously given DBS at 100 µA had a longer latency for the development of epileptiform activity, shorter and smaller DC shifts, and a smaller spike amplitude compared to non-stimulated controls. In contrast, a higher spike amplitude was recorded in slices from animals given AN DBS at 500 µA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0097618PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4043725PMC
January 2015

Social isolation disrupts hippocampal neurogenesis in young non-human primates.

Front Neurosci 2014 27;8:45. Epub 2014 Mar 27.

Departamento de Fisiologia, Universidade Federal de São Paulo São Paulo, Brazil.

Social relationships are crucial for the development and maintenance of normal behavior in non-human primates. Animals that are raised in isolation develop abnormal patterns of behavior that persist even when they are later reunited with their parents. In rodents, social isolation is a stressful event and is associated with a decrease in hippocampal neurogenesis but considerably less is known about the effects of social isolation in non-human primates during the transition from adolescence to adulthood. To investigate how social isolation affects young marmosets, these were isolated from other members of the colony for 1 or 3 weeks and evaluated for alterations in their behavior and hippocampal cell proliferation. We found that anxiety-related behaviors like scent-marking and locomotor activity increased after social isolation when compared to baseline levels. In agreement, grooming-an indicative of attenuation of tension-was reduced among isolated marmosets. These results were consistent with increased cortisol levels after 1 and 3 weeks of isolation. After social isolation (1 or 3 weeks), reduced proliferation of neural cells in the subgranular zone of dentate granule cell layer was identified and a smaller proportion of BrdU-positive cells underwent neuronal fate (doublecortin labeling). Our data is consistent with the notion that social deprivation during the transition from adolescence to adulthood leads to stress and produces anxiety-like behaviors that in turn might affect neurogenesis and contribute to the deleterious consequences of prolonged stressful conditions.
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http://dx.doi.org/10.3389/fnins.2014.00045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3973924PMC
April 2014

Reduced hippocampal manganese-enhanced MRI (MEMRI) signal during pilocarpine-induced status epilepticus: edema or apoptosis?

Epilepsy Res 2014 May 19;108(4):644-52. Epub 2014 Feb 19.

Departamento de Fisiologia, Universidade Federal de São Paulo-UNIFESP, São Paulo 04023-06, SP, Brazil. Electronic address:

Manganese-enhanced MRI (MEMRI) has been considered a surrogate marker of Ca(+2) influx into activated cells and tracer of neuronal active circuits. However, the induction of status epilepticus (SE) by kainic acid does not result in hippocampal MEMRI hypersignal, in spite of its high cell activity. Similarly, short durations of status (5 or 15min) induced by pilocarpine did not alter the hippocampal MEMRI, while 30 min of SE even reduced MEMRI signal Thus, this study was designed to investigate possible explanations for the absence or decrease of MEMRI signal after short periods of SE. We analyzed hippocampal caspase-3 activation (to evaluate apoptosis), T2 relaxometry (tissue water content) and aquaporin 4 expression (water-channel protein) of rats subjected to short periods of pilocarpine-induced SE. For the time periods studied here, apoptotic cell death did not contribute to the decrease of the hippocampal MEMRI signal. However, T2 relaxation was higher in the group of animals subjected to 30min of SE than in the other SE or control groups. This result is consistent with higher AQP-4 expression during the same time period. Based on apoptosis and tissue water content analysis, the low hippocampal MEMRI signal 30min after SE can potentially be attributed to local edema rather than to cell death.
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http://dx.doi.org/10.1016/j.eplepsyres.2014.02.007DOI Listing
May 2014

Participation of bone marrow-derived cells in hippocampal vascularization after status epilepticus.

Seizure 2014 May 30;23(5):386-9. Epub 2014 Jan 30.

Department of Physiology, Federal University of São Paulo, Rua Botucatu, 862, 04023-062 São Paulo, SP, Brazil. Electronic address:

Purpose: Diseases such as temporal lobe epilepsy, brain trauma and stroke can induce endothelial cell proliferation and angiogenesis in specific brain areas. During status epilepticus (SE), bone marrow-derived cells are able to infiltrate and proliferate, dramatically increasing at the site of injury. However, it is still unclear whether these cells directly participate in vascular changes induced by SE.

Method: To investigate the possible role of bone marrow-derived cells in angiogenesis after seizures, we induced SE by pilocarpine injection in previously prepared chimeric mice. Mice were euthanized at 8h, 7d or 15d after SE onset.

Results: Our results indicated that SE modified hippocampal vascularization and induced angiogenesis. Further, bone marrow-derived GFP(+) cells penetrated through the parenchyma and participated in the formation of new vessels after SE. We detected bone marrow-derived cells closely associated with vessels in the hippocampus, increasing the density of blood vessels that had decreased immediately after pilocarpine-induced SE.

Conclusion: We conclude that epileptic seizures directly affect vascularization in the hippocampus mediated by bone marrow-derived cells in a time-dependent manner.
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http://dx.doi.org/10.1016/j.seizure.2014.01.017DOI Listing
May 2014

Sex-related long-term behavioral and hippocampal cellular alterations after nociceptive stimulation throughout postnatal development in rats.

Neuropharmacology 2014 Feb 19;77:268-76. Epub 2013 Oct 19.

Departamento de Fisiologia, Universidade Federal de São Paulo, São Paulo, SP 04023-062, Brazil. Electronic address:

Early noxious stimuli may alter the neurogenesis rate in the dentate gyrus and the behavioral repertoire of adult rats. This study evaluated the long-term effects of noxious stimulation, imposed in different phases of development, on nociceptive and anxiety-like behaviors, hippocampal activation, cell proliferation, hippocampal BDNF and plasma corticosterone levels in 40 day-old male and female adolescents. Noxious stimulation was induced by intra-plantar injection of Complete Freund's adjuvant (CFA), on postnatal days (P) 1 (group P1), 8 (P8) or 21 (P21). Control animals were not stimulated in any way. On P21 a subset of animals from each group received BrdU and was perfused on P40 for identification of proliferating cells in the granule cell layer of the dentate gyrus. Another subset of rats was subjected to behavioral testing on P40 and one week later, to magnetic resonance imaging (MRI) acquisition. Noxious stimulation evoked hypoalgesia in adolescents, mainly in females (P < 0.02), reflected by greater latency to withdraw the paw and less paw lickings in the hot plate test than controls (P < 0.001). It also resulted in more time spent in the open arms, e.g., less anxiety-like behavior than controls (P < 0.01), especially in females (P < 0.01, compared with males). Proliferative cell rate in the dentate gyrus was the highest in P8 males and females (P < 0.001), with males exhibiting more proliferation than females on P1 and P8, which was directly related to the hippocampal levels of BDNF and inversely related to plasma corticosterone. Sex differences were also detected in manganese-enhanced MRI signal, which was more prominent in P1 females than males (P < 0.01). This study represents the first step of investigation on the cellular basis of the sex-dependent long-term consequences of nociceptive stimuli in newborns.
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http://dx.doi.org/10.1016/j.neuropharm.2013.10.007DOI Listing
February 2014

Reduced hippocampal dentate cell proliferation and impaired spatial memory performance in aged-epileptic rats.

Front Neurol 2013 26;4:106. Epub 2013 Jul 26.

Department of Physiology, Universidade Federal de São Paulo - UNIFESP , São Paulo , Brazil.

Increased adult neurogenesis is observed after training in hippocampal-dependent tasks and also after acutely induced status epilepticus (SE) although the specific roles of these cells are still a matter of debate. In this study, we investigated hippocampal cell proliferation and differentiation and the spatial learning performance in young or aged chronically epileptic rats. Status was induced by pilocarpine in 3 or 20-month old rats. Either 2 or 20 months later, rats were treated with bromodeoxyuridine (BrdU) and subsequently underwent to 8-day schedule of water maze (WM) tests. As expected, learning curves were faster in young than in aged animals (P < 0.001). Chronically epileptic animals exhibited impaired learning curves compared to age-matched controls. Interestingly, the duration of epilepsy (2 or 20 months) did not correlate with the memory impairment of aged-epileptic animals. The number of BrdU-positive cells was greater in young-epileptic subjects than in age-matched controls. In contrast, cell proliferation was not increased in aged-epileptic animals, irrespective of the time of SE induction. Finally, dentate cell proliferation was not related to performance in the WM. Based on the present results we conclude that even though aging and epilepsy lead to impairments in spatial learning, their effects are not additive.
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http://dx.doi.org/10.3389/fneur.2013.00106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724058PMC
July 2013
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