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1.
Methods Mol Biol ; 2191: 201-220, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32865747

RESUMO

Zebrafish are an excellent model organism to study many aspects of vertebrate sensory encoding and behavior. Their escape responses begin with a C-shaped body bend followed by several swimming bouts away from the potentially threatening stimulus. This highly stereotyped motor behavior provides a model for studying startle reflexes and the neural circuitry underlying multisensory encoding and locomotion. Channelrhodopsin (ChR2) can be expressed in the lateral line and ear hair cells of zebrafish and can be excited in vivo to elicit these rapid forms of escape. Here we review our methods for studying transgenic ChR2-expressing zebrafish larvae, including screening for positive expression of ChR2 and recording field potentials and high-speed videos of optically evoked escape responses. We also highlight important features of the acquired data and provide a brief review of other zebrafish research that utilizes or has the potential to benefit from ChR2 and optogenetics.


Assuntos
Channelrhodopsins/genética , Potenciais Evocados/genética , Neurônios/metabolismo , Optogenética/métodos , Animais , Animais Geneticamente Modificados/genética , Channelrhodopsins/fisiologia , Potenciais Evocados/fisiologia , Células Ciliadas Auditivas/metabolismo , Larva/fisiologia , Locomoção/genética , Locomoção/fisiologia , Neurônios/patologia , Reflexo de Sobressalto/fisiologia , Natação/fisiologia , Peixe-Zebra/genética , Peixe-Zebra/fisiologia
2.
J Vis Exp ; (161)2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32716380

RESUMO

While there is an abundance of commercial and standardized automated systems and software for performing the prepulse inhibition (PPI) assay in rodents, to the best of our knowledge, all PPI assays performed in the zebrafish have, until now, been done using custom made systems which were only available to individual groups. This has thereby presented challenges, particularly with regard to issues of data reproducibility and standardization. In the present work, we generated a protocol that utilizes commercially available automated systems to pharmacologically validate the PPI assay in larval zebrafish. Consistent with published findings, we were able to replicate the results of apomorphine, haloperidol and ketamine on the PPI response of 6 days post-fertilization zebrafish larvae.


Assuntos
Larva/efeitos dos fármacos , Inibição Pré-Pulso/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Animais , Masculino , Reprodutibilidade dos Testes , Peixe-Zebra
3.
Psychopharmacology (Berl) ; 237(7): 2161-2172, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32363439

RESUMO

The ability to discriminate between danger and safety is crucial for survival across species. Whereas danger signals predict the onset of a potentially threatening event, safety signals indicate the non-occurrence of an aversive event, thereby reducing fear and stress responses. While the neural basis of conditioned safety remains to be elucidated, fear extinction studies provide evidence that the infralimbic cortex (IL) modulates fear inhibition. In the current study, the IL was temporarily inactivated with local muscimol injections in male and female rats. The effect of IL inactivation on the acquisition and expression of conditioned safety was investigated utilizing the startle response. Temporary inactivation of the IL prior to conditioning did not affect the acquisition of conditioned safety, whereas IL inactivation during the expression test completely blocked the expression of conditioned safety in male and female rats. Inactivation of the neighboring prelimbic (PL) cortex during the expression test did not affect the expression of safety memory. Our findings suggest that the IL is a critical brain region for the expression of safety memory. Because patients suffering from anxiety disorders are often unable to make use of safety cues to inhibit fear, the present findings are of clinical relevance and could potentially contribute to therapy optimization of anxiety-related psychiatric disorders.


Assuntos
Condicionamento Clássico/fisiologia , Medo/fisiologia , Inibição Psicológica , Memória/fisiologia , Córtex Pré-Frontal/metabolismo , Reflexo de Sobressalto/fisiologia , Animais , Condicionamento Clássico/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Medo/efeitos dos fármacos , Medo/psicologia , Feminino , Agonistas de Receptores de GABA-A/farmacologia , Masculino , Memória/efeitos dos fármacos , Muscimol/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Reflexo de Sobressalto/efeitos dos fármacos
4.
J Vis Exp ; (158)2020 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-32391817

RESUMO

Animal temperament is complex and has implications for productivity and economic profitability. Quantifying an animal's response to differing stimuli may facilitate breeding selections and identify animals that are better suited to specific management strategies. Multiple tests have been developed to evaluate cattle temperament (e.g., exit velocity, chute score, pen score, open field test, startle test, bovine zero maze), but each of these tests evaluates the animal's response to different stimuli (e.g., isolation, novel environment, startle, willingness to enter an enclosed area). Cattle temperament has been observed to be relatively stable over time. However, the evaluation of temperament has the potential to be influenced by current conditions, previous experiences, and observer bias. Many of these temperament tests have been improperly categorized as fear tests and have also been criticized for being subjective. This paper provides a framework for standardizing behavioral tests for cattle and suggests that these different evaluations assess different aspects of the animal's overall temperament.


Assuntos
Bovinos/psicologia , Medo/fisiologia , Animais , Comportamento Animal/fisiologia , Encéfalo/fisiologia , Análise por Conglomerados , Feminino , Masculino , Aprendizagem em Labirinto , Análise Multivariada , Reflexo de Sobressalto/fisiologia , Temperamento/fisiologia
5.
Psychopharmacology (Berl) ; 237(6): 1643-1655, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32095916

RESUMO

RATIONALE: Prepulse inhibition of the startle reflex (PPI) is disrupted in several psychiatric disorders including schizophrenia. Understanding PPI pharmacology may help elucidate the pathophysiology of these disorders and lead to better treatments. Given the advantages of multi-target approaches for complex mental illnesses treatment, we have investigated the interaction between receptors known to modulate PPI (5-HT1A and 5-HT2A) and the neuromodulatory endocannabinoid system. OBJECTIVES: To investigate serotonin and cannabinoid receptor (CBR) co-modulation in a model of PPI disruption relevant to schizophrenia METHODS: Male Swiss mice were pretreated with WIN 55,212-2 (CBR agonist), rimonabant (CB1R inverse agonist), 8-OH-DPAT (5-HT1A/7 agonist), and volinanserin (5-HT2A antagonist) or with a combination of a cannabinoid and a serotonergic drug. PPI disruption was induced by acute administration of MK-801. RESULTS: WIN 55,212-2 and rimonabant did not change PPI nor block MK-801-induced deficits. 8-OH-DPAT increased PPI in control mice and, in a higher dose, inhibited MK-801-induced impairments. Volinanserin also increased PPI in control and MK-801-treated mice, presenting an inverted U-shaped dose-response curve. Co-administration of either cannabinoid ligand with 8-OH-DPAT did not change PPI; however, the combination of volinanserin with rimonabant increased PPI in both control and MK-801-exposed mice. CONCLUSIONS: WIN 55,212-2 and rimonabant had similar effects in PPI. Moreover, serotonin and cannabinoid receptors interact to modulate PPI. While co-modulation of CBR and 5-HT1A receptors did not change PPI, a beneficial effect of 5-HT2A and CB1R antagonist combination was detected, possibly mediated through potentiation of 5-HT2A blockade effects by concomitant CB1R blockade.


Assuntos
Antagonistas de Receptores de Canabinoides/administração & dosagem , Inibição Pré-Pulso/fisiologia , Receptor 5-HT2A de Serotonina/fisiologia , Receptores de Canabinoides/fisiologia , Esquizofrenia/tratamento farmacológico , Antagonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , 8-Hidroxi-2-(di-n-propilamino)tetralina/administração & dosagem , Animais , Benzoxazinas/administração & dosagem , Moduladores de Receptores de Canabinoides/administração & dosagem , Canabinoides/administração & dosagem , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Fluorbenzenos/administração & dosagem , Masculino , Camundongos , Morfolinas/administração & dosagem , Naftalenos/administração & dosagem , Piperidinas/administração & dosagem , Inibição Pré-Pulso/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Agonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Resultado do Tratamento
6.
Ageing Res Rev ; 59: 101028, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32092463

RESUMO

Inhibition plays a crucial role in many functional domains, such as cognition, emotion, and actions. Studies on cognitive aging demonstrate changes in inhibitory mechanisms are age- and pathology-related. Prepulse inhibition (PPI) is the suppression of an acoustic startle reflex (ASR) to an intense stimulus when a weak prepulse stimulus precedes the startle stimulus. A reduction of PPI is thought to reflect dysfunction of sensorimotor gating which normally suppresses excessive behavioral responses to disruptive stimuli. Both human and rodent studies show age-dependent alterations of PPI of the ASR that are further compromised in Alzheimer's disease (AD). The auditory P50 gating, an index of repetition suppression, also is characterized as a putative electrophysiological biomarker of prodromal AD. This review provides the latest evidence of age- and AD-associated impairment of sensorimotor gating based upon both human and rodent studies, as well as the AD-related disruption of P50 gating in humans. It begins with a concise review of neural networks underlying PPI regulation. Then, evidence of age- and AD-related dysfunction of both PPI and P50 gating is discussed. The attentional/ emotional aspects of sensorimotor gating and the neurotransmitter mechanisms underpinning PPI and P50 gating are also reviewed. The review ends with conclusions and research directions.


Assuntos
Envelhecimento , Doença de Alzheimer/fisiopatologia , Inibição Neural/fisiologia , Reflexo de Sobressalto/fisiologia , Estimulação Acústica/métodos , Humanos , Inibição Pré-Pulso , Tempo de Reação/fisiologia
7.
Sci Rep ; 10(1): 1529, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-32001763

RESUMO

Inhibiting fear-related thoughts and defensive behaviors when they are no longer appropriate to the situation is a prerequisite for flexible and adaptive responding to changing environments. Such inhibition of defensive systems is mediated by ventromedial prefrontal cortex (vmPFC), limbic basolateral amygdala (BLA), and brain stem locus-coeruleus noradrenergic system (LC-NAs). Non-invasive, transcutaneous vagus nerve stimulation (tVNS) has shown to activate this circuit. Using a multiple-day single-cue fear conditioning and extinction paradigm, we investigated long-term effects of tVNS on inhibition of low-level amygdala modulated fear potentiated startle and cognitive risk assessments. We found that administration of tVNS during extinction training facilitated inhibition of fear potentiated startle responses and cognitive risk assessments, resulting in facilitated formation, consolidation and long-term recall of extinction memory, and prevention of the return of fear. These findings might indicate new ways to increase the efficacy of exposure-based treatments of anxiety disorders.


Assuntos
Extinção Psicológica/fisiologia , Medo/fisiologia , Estimulação Elétrica Nervosa Transcutânea/métodos , Adolescente , Adulto , Tonsila do Cerebelo/fisiologia , Condicionamento Clássico/fisiologia , Medo/psicologia , Feminino , Humanos , Inibição Psicológica , Masculino , Memória/fisiologia , Córtex Pré-Frontal/fisiologia , Reflexo de Sobressalto/fisiologia , Nervo Vago/metabolismo , Nervo Vago/fisiologia , Estimulação do Nervo Vago/métodos , Adulto Jovem
8.
Psychopharmacology (Berl) ; 237(5): 1397-1405, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31993694

RESUMO

RATIONALE: Impaired cerebral glucose metabolism is a core pathological feature of schizophrenia. We recently demonstrated that a ketogenic diet, causing a shift from glycolysis to ketosis, normalized schizophrenia-like behaviours in an acute N-methyl-D-aspartate (NMDA) receptor antagonist model of the illness. Ketogenic diet produces the ketone body, ß-hydroxybutyrate (BHB), which may serve as an alternative fuel source in its own right without a strict dietary regime. OBJECTIVE: We hypothesized that chronic administration of BHB replicates the therapeutic effects of ketogenic diet in an acute NMDA receptor hypofunction model of schizophrenia in mice. METHODS: C57Bl/6 mice were either treated with acute doses of 2 mmol/kg, 10 mmol/kg, or 20 mmol/kg BHB or received daily intraperitoneal injections of 2 mmol/kg BHB or saline for 3 weeks. Behavioural testing assessed the effect of acute challenge with 0.2 mg/kg MK-801 or saline on open field behaviour, social interaction, and prepulse inhibition of startle (PPI). RESULTS: Acute BHB administration dose-dependently increased BHB plasma levels, whereas the 2 mmol/kg dose increased plasma glucose levels. The highest acute dose of BHB supressed spontaneous locomotor activity, MK-801-induced locomotor hyperactivity and MK-801-induced disruption of PPI. Chronic BHB treatment normalized MK-801-induced hyperlocomotion, reduction of sociability, and disruption of PPI. CONCLUSION: In conclusion, BHB may present a novel treatment option for patients with schizophrenia by providing an alternative fuel source to normalize impaired glucose metabolism in the brain.


Assuntos
Ácido 3-Hidroxibutírico/uso terapêutico , Maleato de Dizocilpina/toxicidade , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Ácido 3-Hidroxibutírico/farmacologia , Animais , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/toxicidade , Injeções Intraperitoneais , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Inibição Pré-Pulso/efeitos dos fármacos , Inibição Pré-Pulso/fisiologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/fisiologia , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Resultado do Tratamento
9.
Psychopharmacology (Berl) ; 237(5): 1305-1315, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31984446

RESUMO

RATIONALE: To demonstrate that repeated episodes of binge drinking during the adolescent period can lead to long-term deficits in motor function and memory in adulthood, and increase proteins in the brain involved with inflammation and apoptotic cell death. METHODS: Groups of early adolescent (PND 26) and periadolescent (PND 34) Sprague-Dawley rats were exposed to either ethanol or plain air through a vapor chamber apparatus for five consecutive days (2 h per day), achieving a blood ethanol concentration equivalent to 6-8 drinks in the treatment group. Subjects then underwent a series of behavioral tests designed to assess memory, anxiety regulation, and motor function. Brains were collected on PND 94 for subsequent western blot analysis. RESULTS: Behavioral testing using the rota-rod, cage-hang, novel object recognition, light-dark box, and elevated plus maze apparatuses showed significant differences between groups; several of which persisted for up to 60 days after treatment. Western blot testing indicated elevated levels of caspase-3/cleaved caspase-3, NF-kB, and PKC/pPKC proteins in the cerebella of ethanol-treated animals. CONCLUSIONS: Differences on anxiety tests indicate a possible failure of behavioral inhibition in the treatment group leading to riskier behavior. Binge drinking also impairs motor coordination and object memory, which involve the cerebellar and hippocampal brain regions, respectively. These experiments indicate the potential dangers of binge drinking while the brain is still developing and indicate the need for future studies in this area.


Assuntos
Apoptose/fisiologia , Bebedeira/metabolismo , Bebedeira/psicologia , Cerebelo/metabolismo , Etanol/administração & dosagem , Mediadores da Inflamação/metabolismo , Administração por Inalação , Fatores Etários , Animais , Apoptose/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Etanol/toxicidade , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Ratos , Ratos Sprague-Dawley , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia
10.
Psychol Res ; 84(1): 15-22, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29455232

RESUMO

The current research was designed to assess possible differences in the emotional content of pleasant and unpleasant face emoji using acoustically evoked eyeblink startle reflex response. Stimuli were selected from Emojipedia Webpage. First, we assessed these stimuli with a previous independent sample of 190 undergraduate students (46 males and 144 females) mean age of 21.43 years (SD 3.89). A principal axis method was performed using the 30 selected emoji faces, extracting two factors (15 pleasant and 15 unpleasant emoji). Second, we measured the acoustic startle reflex modulation in 53 young adult women [mean age 22.13 years (SD 4.3)] during the viewing of each of the 30 emoji emotional faces in the context of the theory of motivation and emotion proposed by Lang (1995), but considering only the valence dimension. We expected to find higher acoustically evoked startle responses when viewing unpleasant emoji and lower responses for pleasant ones, similarly to the results obtained in the studies using human faces as emotional stimulus. An ANOVA was conducted to compare acoustic startle responses associated with pleasant and unpleasant emoji. Results yielded main effects for picture valence (λ = 0.80, F(1, 50) = 12.80, p = .001, η2 = 0.20). Post-hoc t test analysis indicated significant differences in the startle response between unpleasant (50.95 ± 1.75) and pleasant (49.14 ± 2.49) emoji (t (52) = 3.59, p = .001), with a Cohen's d = 0.495. Viewing affective facial emoji expressions modulates the acoustic startle reflex response according to their emotional content.


Assuntos
Piscadela/fisiologia , Emoções/fisiologia , Estimulação Luminosa , Reflexo de Sobressalto/fisiologia , Mídias Sociais , Adulto , Feminino , Humanos , Espanha , Adulto Jovem
11.
Genes Brain Behav ; 19(2): e12604, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31412164

RESUMO

Amyotrophic lateral sclerosis (ALS) involves the rapid degeneration of upper and lower motor neurons leading to weakening and paralysis of voluntary movements. Mutations in copper-zinc superoxide dismutase 1 (SOD1) are a known genetic cause of ALS, and the SOD1 G93A mouse has been used extensively to investigate molecular mechanisms in ALS. In recent years, evidence suggests that ALS and frontotemporal dementia form a spectrum disorder ranging from motor to cognitive dysfunctions. Thus, we tested male and female SOD1 G93A mice for the first time before the onset of debilitating motor impairments in behavioural domains relevant to both ALS and frontotemporal dementia. SOD1 G93A males displayed reduced locomotion, exploration and increased anxiety-like behaviours compared with control males. Intermediate-term spatial memory was impaired in SOD1 G93A females, whereas long-term spatial memory deficits as well as lower acoustic startle response, and prepulse inhibition were identified in SOD1 G93A mice of both sexes compared with respective controls. Interestingly, SOD1 G93A males exhibited an increased conditioned cue freezing response. Nosing behaviours were also elevated in both male and female SOD1 G93A when assessed in social paradigms. In conclusion, SOD1 G93A mice exhibit a variety of sex-specific behavioural deficits beyond motor impairments supporting the notion of an ALS-frontotemporal spectrum disorder. Thus, SOD1 G93A mice may represent a useful model to test the efficacy of therapeutic interventions on clinical symptoms in addition to declining motor abilities.


Assuntos
Esclerose Amiotrófica Lateral/fisiopatologia , Superóxido Dismutase/genética , Esclerose Amiotrófica Lateral/genética , Animais , Ansiedade/fisiopatologia , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Feminino , Demência Frontotemporal/genética , Demência Frontotemporal/fisiopatologia , Humanos , Locomoção , Masculino , Camundongos , Camundongos Transgênicos , Neurônios Motores , Mutação , Fenótipo , Reflexo de Sobressalto/fisiologia , Fatores Sexuais , Medula Espinal , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo
12.
J Vis Exp ; (152)2019 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-31710027

RESUMO

Conductive hearing loss (CHL) is a prevalent hearing impairment in humans. The goal of the protocol is to describe a simple surgical procedure for inducing CHL in rodents. The protocol demonstrates CHL by tympanic membrane puncture. Verification of CHL surgery was by otoscope examination and behavioral assessment by clap startle response, both replicable and reliable, and are simple methods to demonstrate hearing loss has occurred. The simple CHL procedure is advantageous due to its reproducibility and flexibility to different pursuits in hearing loss research. The limitations of inducing CHL by a surgical approach are associated with the learning curve to perform the surgical procedure and confidence in audiological examination. Inducing a hearing impairment by CHL allows one to readily study the neural manifestations and behavioral outcomes of hearing loss.


Assuntos
Perda Auditiva Condutiva/cirurgia , Otoscópios/normas , Reflexo de Sobressalto/fisiologia , Animais , Feminino , Humanos , Masculino , Ratos , Ratos Sprague-Dawley
13.
Bull Exp Biol Med ; 168(2): 300-303, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31776950

RESUMO

Phenotypical study was carried out in rats with pendulum movements. The animals exhibited a high level of abortive seizures in response to audiogenic stimuli and longer postictal catalepsy in comparison with those in Wistar population. Seizure severity positively correlated with the duration of poststimulus catalepsy (r=0.90). High aggressiveness towards humans, the absence of BP elevation in stress, lower body weights, and lower weights of the kidneys and spleen in PM rats are considered concomitant traits. Correlations were detected between startle-1 and BP in rats with pendulum movements (r=0.70) and between startle-10 and BP in narcotized Wistar rats (r=-0.0.71). The newly described signs in rats with pendulum movements did not contradict the signs of the focal seizure model with typical automatisms in humans.


Assuntos
Automatismo/fisiopatologia , Reflexo de Sobressalto/fisiologia , Convulsões/patologia , Estimulação Acústica , Animais , Pressão Sanguínea/fisiologia , Catalepsia/fisiopatologia , Rim/fisiopatologia , Movimento/fisiologia , Ratos , Ratos Wistar , Baço/fisiopatologia
14.
J Clin Neurophysiol ; 36(6): 452-459, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31688329

RESUMO

It has been well documented that a prepared response can be triggered at short latency following the presentation of a loud acoustic stimulus that evokes a reflexive startle response. Different hypotheses have been proposed for this so-called "StartReact" effect, although there is still much debate surrounding the physiological mechanisms involved in the observed reduction in reaction time (RT). In this review, we outline the various neurophysiological explanations underlying the StartReact effect and summarize the data supporting, and at times opposing, each possibility. Collectively, the experimental results do not unequivocally support a single explanation and we suggest the most parsimonious mechanism may involve a hybrid framework involving a distribution of neural pathways. Specifically, we propose that multiple node networks at the cortical, brainstem, and spinal levels are involved in response preparation and initiation, and the relative contributions of these structures depends on the type of stimulus delivered and the type of movement required. This approach may lead to greater understanding of the pathways involved in response preparation, initiation, and execution for both healthy and motor disordered populations.


Assuntos
Tempo de Reação/fisiologia , Reflexo de Sobressalto/fisiologia , Estimulação Acústica/métodos , Feminino , Humanos , Masculino , Movimento/fisiologia
15.
Behav Res Ther ; 122: 103461, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31585344

RESUMO

The procedure of memory reconsolidation provides an opportunity to improve some mental disorders caused by maladaptive memories, such as Posttraumatic Stress Disorder. Prediction error was considered a necessary condition for triggering memory reconsolidation. However, it is difficult to create a satisfying prediction error to successfully open memory reconsolidation in a clinical context. The purpose of this study was to explore a more practicable method to trigger memory reconsolidation. We used a successive 4-day fear-potentiated startle paradigm to compare the effect of uncertainty with prediction error during retrieval on preventing the return of fear. Bayes factor, combined with p value and effect size, was used as the main indicator of statistical inference. The results indicated that spontaneous recovery and reinstatement of fear were not observed in the uncertainty group, whereas return of fear was observed for the prediction error group. However, the direct comparison between the two groups did not yield statistically significant results, potentially reflecting a lack of statistical power. Nonetheless, these results suggest that uncertainty retrieval could be a better means to trigger memory reconsolidation than prediction error, making uncertainty a worthwhile factor to consider in future research on memory reconsolidation.


Assuntos
Condicionamento Clássico/fisiologia , Medo/psicologia , Consolidação da Memória/fisiologia , Reflexo de Sobressalto/fisiologia , Adolescente , Adulto , Extinção Psicológica/fisiologia , Feminino , Humanos , Masculino , Adulto Jovem
16.
J Neuroinflammation ; 16(1): 194, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-31660990

RESUMO

BACKGROUND: Hypoxic-ischemic (HI) encephalopathy causes life-long morbidity and premature mortality in term neonates. Therapies in addition to whole-body cooling are under development to treat the neonate at risk for HI encephalopathy, but are not a quickly measured serum inflammatory or neuronal biomarkers to rapidly and accurately identify brain injury in order to follow the efficacy of therapies. METHODS: In order to identify potential biomarkers for early inflammatory and neurodegenerative events after neonatal hypoxia-ischemia, both male and female Wistar rat pups at postnatal day 7 (P7) were used and had their right carotid artery permanently doubly occluded and exposed to 8% oxygen for 90 min. Sensory and cognitive parameters were assessed by open field, rotarod, CatWalk, and Morris water maze (MWM) test. Plasma and CSF biomarkers were investigated on the acute (24 h and 72 h) and chronic phase (4 weeks). Brains were assessed for gene expression analysis by quantitative RT-PCR Array. RESULTS: We found a delay of neurological reflex maturation in HI rats. We observed anxiolytic-like baseline behavior in males more than females following HI injury. HI rats held on the rotarod for a shorter time comparing to sham. HI injury impaired spatial learning ability on MWM test. The CatWalk assessment demonstrated a long-term deficit in gait parameters related to the hind paw. Proinflammatory biomarkers such as IL-6 in plasma and CCL2 and TNF-α in CSF showed an upregulation at 24 h after HI while other cytokines, such as IL-17A and CCL5, were upregulated after 72 h in CSF. At 24 h post-injury, we observed an increase of Edn1, Hif1-α, and Mmp9 mRNA levels in the ipsilateral vs the contralateral hemisphere of HI rats. An upregulation of genes involved with clotting and hematopoietic processes was observed 72 h post-injury. CONCLUSIONS: Our work showed that, in the immature brain, the HI injury induced an early increased production of several proinflammatory mediators detectable in plasma and CSF, followed by tissue damage in the hypoxic hemisphere and short-term as well as long-lasting neurobehavioral deficits.


Assuntos
Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/patologia , Mediadores da Inflamação/metabolismo , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Animais , Animais Recém-Nascidos , Biomarcadores/metabolismo , Feminino , Masculino , Aprendizagem em Labirinto/fisiologia , Distribuição Aleatória , Ratos , Ratos Wistar , Reflexo de Sobressalto/fisiologia , Fatores de Tempo
17.
J Neurosci ; 39(47): 9424-9434, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31615840

RESUMO

Associative memory can be rendered malleable by a reminder. Blocking the ensuing reconsolidation process is suggested as a therapeutic target for unwanted aversive memories. Matrix metalloproteinase-9 (MMP-9) is required for structural synapse remodeling involved in memory consolidation. Inhibiting MMP-9 with doxycycline is suggested to attenuate human threat conditioning. Here, we investigated whether MMP-9 inhibition also interferes with threat memory reconsolidation. Male and female human participants (N = 78) learned the association between two visual conditioned stimuli (CS+) and a 50% chance of an unconditioned nociceptive stimulus (US), and between CS- and the absence of US. On day 7, one CS+ was reminded without reinforcement 3.5 h after ingesting either 200 mg of doxycycline or placebo. On day 14, retention of CS memory was assessed under extinction by fear-potentiated startle. Contrary to our expectations, we observed a greater CS+/CS- difference in participants who were reminded under doxycycline compared with placebo. Participants who were reminded under placebo showed extinction learning during the retention test, which was not observed in the doxycycline group. There was no difference between the reminded and the nonreminded CS+ in either group. In contrast, during relearning after the retention test, the CS+/CS- difference was more pronounced in the placebo group than in the doxycycline group. To summarize, a single dose of doxycycline before threat memory reminder appeared to have no specific impact on reconsolidation, but to globally impair extinction learning, and threat relearning, beyond drug clearance.SIGNIFICANCE STATEMENT Matrix metalloproteinase-9 inhibition appears to attenuate memory consolidation. It could also be a target for blocking reconsolidation. Here, we test this hypothesis in human threat conditioning. We find that doxycycline has no specific impact on a reminded cue, but confers a global reduction in extinction learning and threat learning beyond the clearance of the drug. This may point toward a more long-lasting impact of doxycycline treatment on memory plasticity.


Assuntos
Doxiciclina/farmacologia , Medo/efeitos dos fármacos , Metaloproteinase 9 da Matriz/metabolismo , Inibidores de Metaloproteinases de Matriz/farmacologia , Memória/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Adulto , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Medo/fisiologia , Medo/psicologia , Feminino , Humanos , Masculino , Memória/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Distribuição Aleatória , Reflexo de Sobressalto/efeitos dos fármacos , Adulto Jovem
18.
J Neurophysiol ; 122(6): 2541-2547, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31642402

RESUMO

The "StartReact" effect refers to the rapid involuntary triggering of a prepared movement in response to a loud startling acoustic stimulus (SAS). This effect is typically confirmed by the presence of short-latency electromyographic activity in startle reflex-related muscles such as the sternocleidomastoid (SCM); however, there is debate regarding the specific neural pathways involved in the StartReact effect. Some research has implicated a subcortically mediated pathway, which would predict different response latencies depending on the presence of a startle reflex. Alternatively, other research has suggested that this effect involves the same pathways responsible for voluntary response initiation and simply reflects higher preparatory activation levels, and thus faster voluntary initiation. To distinguish between these competing hypotheses, the present study assessed preparation level during a simple reaction time (RT) task involving wrist extension in response to a control tone or a SAS. Premotor RT and startle circuitry engagement (as measured by SCM activation) were determined for each trial. Additionally, preparation level at the go signal on each trial was measured using motor-evoked potentials (MEP) elicited by transcranial magnetic stimulation (TMS). Results showed that SAS trial RTs were significantly shorter (P = 0.009) in the presence of startle-related SCM activity. Nevertheless, preparation levels (as indexed by MEP amplitude) were statistically equivalent between trials with and without SCM activation. These results indicate that the StartReact effect relates to engagement of the startle reflex circuitry rather than simply being a result of an increased level of preparatory activation.NEW & NOTEWORTHY The neural mechanism underlying the early triggering of goal-directed actions by a startling acoustic stimulus (SAS) is unclear. We show that although significant reaction time differences were evident depending on whether the SAS elicited a startle reflex, motor preparatory activation was the same. Thus, in a highly prepared state, the short-latency responses associated with the StartReact effect appear to be related to engagement of startle reflex circuitry, not differences in motor preparatory level.


Assuntos
Potencial Evocado Motor/fisiologia , Atividade Motora/fisiologia , Vias Neurais/fisiologia , Tempo de Reação/fisiologia , Reflexo de Sobressalto/fisiologia , Estimulação Acústica , Adulto , Feminino , Humanos , Masculino , Estimulação Magnética Transcraniana , Adulto Jovem
19.
BMC Psychiatry ; 19(1): 282, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31510965

RESUMO

BACKGROUND: Prepulse inhibition (PPI) is a measurement method for the sensory gating process, which helps the brain adapt to complex environments. PPI may be reduced in patients with bipolar disorder (BD). This study investigated PPI deficits in BD and pooled the effect size of PPI in patients with BD. METHODS: We conducted a literature search on PPI in patients with BD from inception to July 27, 2019 in PubMed, Embase, Cochrane Library databases, and Chinese databases. No age, sex, and language restriction were set. The calculation formula was PPI = 100 - [100*((prepulse - pulse amplitude) / pulse amplitude)]. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of studies. RESULTS: Ten eligible papers were identified, of which five studies including a total of 141 euthymic patients and 132 healthy controls (HC) were included in the meta-analysis. Compared with HC, euthymic patients with BD had significantly lower PPI at the 60 ms interstimulus interval (ISI) between pulse and prepulse (P = 0.476, I2 = 0.0%, SMD = - 0.32, 95% CI = - 0.54 - -0.10). Sensitivity analysis shows no significant change in the combined effect value after removing any single study. There was no publication bias using the Egger's test at 60 ms (P = 0.606). The meta-analysis of PPI at the 60 ms ISI could have significant clinical heterogeneity in mood episode state, as well as lack of data on BD I or II subtypes. CONCLUSIONS: Euthymic patients with BD show PPI deficits at the 60 ms, suggesting a deficit in the early sensory gate underlying PPI. The PPI inhibition rate at a 60 ms interval is a stable index. More research is needed in the future to confirm this outcome, and to delve deeper into the mechanisms behind deficits.


Assuntos
Transtorno Bipolar/fisiopatologia , Inibição Pré-Pulso/fisiologia , Reflexo de Sobressalto/fisiologia , Filtro Sensorial/fisiologia , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/psicologia , Transtorno Ciclotímico/diagnóstico , Transtorno Ciclotímico/fisiopatologia , Transtorno Ciclotímico/psicologia , Feminino , Humanos , Masculino
20.
Neurosci Biobehav Rev ; 107: 329-345, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31521698

RESUMO

Translational neuroscience bridges insights from specific mechanisms in rodents to complex functions in humans and is key to advance our general understanding of central nervous function. A prime example of translational research is the study of cross-species mechanisms that underlie responding to learned threats, by employing Pavlovian fear conditioning protocols in rodents and humans. Hitherto, evidence for (and critique of) these cross-species comparisons in fear conditioning research was based on theoretical viewpoints. Here, we provide a perspective to substantiate these theoretical concepts with empirical considerations of cross-species methodology. This meta-research perspective is expected to foster cross-species comparability and reproducibility to ultimately facilitate successful transfer of results from basic science into clinical applications.


Assuntos
Condicionamento Clássico/fisiologia , Extinção Psicológica/fisiologia , Medo/fisiologia , Reflexo de Sobressalto/fisiologia , Humanos , Neurociências , Pesquisa Médica Translacional/métodos
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