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1.
Transl Psychiatry ; 11(1): 233, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888685

RESUMO

Brain-derived neurotrophic factor (BDNF) is implicated in a number of processes that are crucial for healthy functioning of the brain. Schizophrenia is associated with low BDNF levels in the brain and blood, however, not much is known about BDNF's role in the different symptoms of schizophrenia. Here, we used BDNF-haploinsufficient (BDNF+/-) mice to investigate the role of BDNF in different mouse behavioral endophenotypes of schizophrenia. Furthermore, we assessed if an enriched environment can prevent the observed changes. In this study, male mature adult wild-type and BDNF+/- mice were tested in mouse paradigms for cognitive flexibility (attentional set shifting), sensorimotor gating (prepulse inhibition), and associative emotional learning (safety and fear conditioning). Before these tests, half of the mice had a 2-month exposure to an enriched environment, including running wheels. After the tests, BDNF brain levels were quantified. BDNF+/- mice had general deficits in the attentional set-shifting task, increased startle magnitudes, and prepulse inhibition deficits. Contextual fear learning was not affected but safety learning was absent. Enriched environment housing completely prevented the observed behavioral deficits in BDNF+/- mice. Notably, the behavioral performance of the mice was negatively correlated with BDNF protein levels. These novel findings strongly suggest that decreased BDNF levels are associated with several behavioral endophenotypes of schizophrenia. Furthermore, an enriched environment increases BDNF protein to wild-type levels and is thereby able to rescue these behavioral endophenotypes.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Esquizofrenia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Endofenótipos , Haploinsuficiência , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reflexo de Sobressalto , Esquizofrenia/genética
2.
Transl Psychiatry ; 11(1): 241, 2021 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-33895779

RESUMO

Thalamic reticular nucleus (TRN) is a group of inhibitory neurons surrounding the thalamus. Due to its important role in sensory information processing, TRN is considered as the target nucleus for the pathophysiological investigation of schizophrenia and autism spectrum disorder (ASD). Prepulse inhibition (PPI) of acoustic startle response, a phenomenon that strong stimulus-induced startle reflex is reduced by a weaker prestimulus, is always found impaired in schizophrenia and ASD. But the role of TRN in PPI modulation remains unknown. Here, we report that parvalbumin-expressing (PV+) neurons in TRN are activated by sound stimulation of PPI paradigm. Chemogenetic inhibition of PV+ neurons in TRN impairs PPI performance. Further investigations on the mechanism suggest a model of burst-rebound burst firing in TRN-auditory thalamus (medial geniculate nucleus, MG) circuitry. The burst firing is mediated by T-type calcium channel in TRN, and rebound burst firing needs the participation of GABAB receptor in MG. Overall, these findings support the involvement of TRN in PPI modulation.


Assuntos
Transtorno do Espectro Autista , Inibição Pré-Pulso , Acústica , Humanos , Reflexo de Sobressalto , Núcleos Talâmicos
3.
Biol Psychol ; 162: 108094, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33878371

RESUMO

The no, predictable, and unpredictable threat (NPU-threat) task is an experimental paradigm that delineates the anticipation of predictable vs. unpredictable threat. The current literature suggests that heightened defensive motivation in anticipation of unpredictable threat is associated with anxiety disorders and increased symptoms. Few investigations have examined whether a heightened response to actual threat is also associated with anxiety-related phenomenology. The present study examined the relationship between the tactile P300 to shock delivery during the NPU-threat task and individual differences in anxiety symptoms, intolerance of uncertainty, and neuroticism. Overall, the tactile P300 was enhanced in response to unpredictable shocks relative to predictable shocks. Greater tactile P300 enhancement to unpredictable shocks was associated with greater anxiety symptoms, intolerance of uncertainty, and neuroticism. The present study suggests that temporal unpredictability enhances attentional engagement to threat, which is greater in individuals characterized by narrow and broad anxiety constructs.


Assuntos
Antecipação Psicológica , Reflexo de Sobressalto , Ansiedade/etiologia , Humanos , Neuroticismo , Incerteza
4.
Transl Psychiatry ; 11(1): 169, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33723233

RESUMO

Lack of established knowledge and treatment strategies, and change in work environment, may altogether critically affect the mental health and functioning of physicians treating COVID-19 patients. Thus, we examined whether treating COVID-19 patients affect the physicians' mental health differently compared with physicians treating non-COVID-19 patients. In this cohort study, an association was blindly computed between physiologically measured anxiety and attention vigilance (collected from 1 May 2014 to 31 May 31 2016) and self-reports of anxiety, mental health aspects, and sleep quality (collected from 20 April to 30 June 2020, and analyzed from 1 July to 1 September 2020), of 91 physicians treating COVID-19 or non-COVID-19 patients. As a priori hypothesized, physicians treating COVID-19 patients showed a relative elevation in both physiological measures of anxiety (95% CI: 2317.69-2453.44 versus 1982.32-2068.46; P < 0.001) and attention vigilance (95% CI: 29.85-34.97 versus 22.84-26.61; P < 0.001), compared with their colleagues treating non-COVID-19 patients. At least 3 months into the pandemic, physicians treating COVID-19 patients reported high anxiety and low quality of sleep. Machine learning showed clustering to the COVID-19 and non-COVID-19 subgroups with a high correlation mainly between physiological and self-reported anxiety, and between physiologically measured anxiety and sleep duration. To conclude, the pattern of attention vigilance, heightened anxiety, and reduced sleep quality findings point the need for mental intervention aimed at those physicians susceptible to develop post-traumatic stress symptoms, owing to the consequences of fighting at the forefront of the COVID-19 pandemic.


Assuntos
Ansiedade/psicologia , Atenção , COVID-19/terapia , Estresse Ocupacional/psicologia , Médicos/psicologia , Reflexo de Sobressalto , Sono , Transtornos de Estresse Pós-Traumáticos/psicologia , Adulto , Análise por Conglomerados , Feminino , Humanos , Aprendizado de Máquina , Masculino , Saúde Mental , Pessoa de Meia-Idade , SARS-CoV-2
5.
Physiol Behav ; 234: 113372, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33647267

RESUMO

It is unclear whether all animal models of anxiety-like states developed using males are appropriate for use in females. In females, tests involving a learning component might be influenced not only by estrous cycle stage on the test day but also by the stage during the conditioning process. We used two tests - conditioned freezing (CF) and fear potentiated startle (FPS) to compare responsiveness of male rats and females conditioned and/or tested in proestrus (P) or late diestrus (LD). For CF all rats displayed a similar freezing response regardless of sex or estrous cycle stage. In terms of FPS, males and females conditioned in P and tested in P or LD, and females conditioned in LD and tested in LD all showed potentiated startle. The response waned during the test session in males and in females conditioned in P, but not in those conditioned in LD. In contrast, FPS was not apparent in the first half of the test session in females conditioned in LD and tested in P but developed in the second half. We suggest that fear learning during P and LD is robust but may be initially be obscured in rats tested in P because of generalization to the CS due to high estrogen. Estrous cycle stage is an important consideration which must be taken into account in designing behavioural tests in females.


Assuntos
Ciclo Estral , Reflexo de Sobressalto , Animais , Medo , Feminino , Masculino , Proestro , Ratos , Ratos Sprague-Dawley
6.
Transl Psychiatry ; 11(1): 177, 2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33731674

RESUMO

Panic disorder (PD) is characterized by a dysfunctional defensive responding to panic-related body symptoms that is assumed to contribute to the persistence of panic symptomatology. The present study aimed at examining whether this dysfunctional defensive reactivity to panic-related body symptoms would no longer be present following successful cognitive behavior therapy (CBT) but would persist when patients show insufficient symptom improvement. Therefore, in the present study, effects of CBT on reported symptoms and defensive response mobilization during interoceptive challenge were investigated using hyperventilation as a respiratory symptom provocation procedure. Changes in defensive mobilization to body symptoms in the course of CBT were investigated in patients with a primary diagnosis of PD with or without agoraphobia by applying a highly standardized hyperventilation task prior to and after a manual-based CBT (n = 38) or a waiting period (wait-list controls: n = 20). Defensive activation was indexed by the potentiation of the amygdala-dependent startle eyeblink response. All patients showed a pronounced defensive response mobilization to body symptoms at baseline. After treatment, no startle reflex potentiation was found in those patients who showed a clinically significant improvement. However, wait-list controls and treatment non-responders continued to show increased defensive responses to actually innocuous body symptoms after the treatment/waiting period. The present results indicate that the elimination of defensive reactivity to actually innocuous body symptoms might be a neurobiological correlate and indicator of successful CBT in patients with PD, which may help to monitor and optimize CBT outcomes.


Assuntos
Terapia Cognitivo-Comportamental , Transtorno de Pânico , Agorafobia , Humanos , Transtorno de Pânico/terapia , Psicoterapia , Reflexo de Sobressalto , Resultado do Tratamento
7.
Transl Psychiatry ; 11(1): 169, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: covidwho-1135652

RESUMO

Lack of established knowledge and treatment strategies, and change in work environment, may altogether critically affect the mental health and functioning of physicians treating COVID-19 patients. Thus, we examined whether treating COVID-19 patients affect the physicians' mental health differently compared with physicians treating non-COVID-19 patients. In this cohort study, an association was blindly computed between physiologically measured anxiety and attention vigilance (collected from 1 May 2014 to 31 May 31 2016) and self-reports of anxiety, mental health aspects, and sleep quality (collected from 20 April to 30 June 2020, and analyzed from 1 July to 1 September 2020), of 91 physicians treating COVID-19 or non-COVID-19 patients. As a priori hypothesized, physicians treating COVID-19 patients showed a relative elevation in both physiological measures of anxiety (95% CI: 2317.69-2453.44 versus 1982.32-2068.46; P < 0.001) and attention vigilance (95% CI: 29.85-34.97 versus 22.84-26.61; P < 0.001), compared with their colleagues treating non-COVID-19 patients. At least 3 months into the pandemic, physicians treating COVID-19 patients reported high anxiety and low quality of sleep. Machine learning showed clustering to the COVID-19 and non-COVID-19 subgroups with a high correlation mainly between physiological and self-reported anxiety, and between physiologically measured anxiety and sleep duration. To conclude, the pattern of attention vigilance, heightened anxiety, and reduced sleep quality findings point the need for mental intervention aimed at those physicians susceptible to develop post-traumatic stress symptoms, owing to the consequences of fighting at the forefront of the COVID-19 pandemic.


Assuntos
Ansiedade/psicologia , Atenção , COVID-19/terapia , Estresse Ocupacional/psicologia , Médicos/psicologia , Reflexo de Sobressalto , Sono , Transtornos de Estresse Pós-Traumáticos/psicologia , Adulto , Análise por Conglomerados , Feminino , Humanos , Aprendizado de Máquina , Masculino , Saúde Mental , Pessoa de Meia-Idade , SARS-CoV-2
8.
Eur J Pharmacol ; 897: 173949, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33607108

RESUMO

Schizophrenia is a devastating neurodevelopmental disorder. The animal model based on perinatal immune activation, as first-hit, combined with peripubertal stress, as a second hit, has gained evidence in recent years. Omega-3 polyunsaturated fatty acids (n3-PUFAs) is being a promise for schizophrenia prevention. Nevertheless, the influence of sex in schizophrenia neurobiology and prevention has been neglected. Thus, the present study evaluates the preventive effects of n3-PUFAs in both sexes' mice submitted to the two-hit model and the participation of oxidative changes in this mechanism. The two-hit consisted of polyI:C administration from postnatal days (PNs) 5-7, and unpredictable stress from PNs35-43. n3-PUFAs were administered from PNs30-60. Prepulse inhibition of the startle reflex (PPI), social interaction, and Y-maze tests were conducted between PNs70-72 to evaluate positive-, negative-, and cognitive-like schizophrenia symptoms. We assessed brain oxidative changes in brain areas and plasma. Both sexes' two-hit mice presented deficits in PPI, social interaction, and working memory that were prevented by n3-PUFAs. In two-hit females, n3-PUFAs prevented increments in nitrite levels in the prefrontal cortex (PFC), hippocampus, striatum, and plasma TBARS levels. In two-hit males, n3-PUFAs prevented the increase in TBARS in the PFC, hippocampus, and striatum. Notably, male mice that received only n3-PUFAs without hit exposure presented impairments in working memory and social interaction. These results add further preclinical evidence for n3-PUFAs as an accessible and effective alternative in preventing behavioral and oxidative changes related to schizophrenia but call attention to the need for precaution in this indication due to hit- and sex-sensitive issues.


Assuntos
Antioxidantes/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Ácidos Graxos Ômega-3/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Esquizofrenia/prevenção & controle , Psicologia do Esquizofrênico , Fatores Etários , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Suplementos Nutricionais , Modelos Animais de Doenças , Feminino , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Poli I-C , Inibição Pré-Pulso/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Esquizofrenia/etiologia , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia , Fatores Sexuais , Desenvolvimento Sexual , Comportamento Social , Estresse Psicológico/complicações
9.
Biomolecules ; 11(2)2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33525455

RESUMO

Tourette syndrome (TS) is a disabling neurodevelopmental disorder characterized by multiple, recurrent tics. The pharmacological treatment of TS is currently based on dopaminergic antagonists; however, these drugs are associated with extrapyramidal symptoms and other serious adverse events. Recent evidence suggests that positive allosteric modulators (PAMs) of GABAA receptors containing α6 subunits (α6 GABAARs) oppose the behavioral effects of dopamine. Building on this evidence, in the present study, we tested the efficacy of DK-I-56-1, a highly selective PAM for α6 GABAARs, in mouse models of TS exhibiting tic-related responses. DK-I-56-1 significantly reduced tic-like jerks and prepulse inhibition (PPI) deficits in D1CT-7 transgenic mice, a well-documented mouse model of TS. DK-I-56-1 also prevented the exacerbation of spontaneous eyeblink reflex induced by the potent dopamine D1 receptor agonist SKF 82958, a proxy for tic-like responses. We also showed that both systemic and prefrontal cortical administration of DK-I-56-1 countered the PPI disruption caused by SKF 82958. Although the effects of DK-I-56-1 were akin to those elicited by dopaminergic antagonists, this drug did not elicit extrapyramidal effects, as measured by catalepsy. These results point to α6 GABAAR PAMs as promising TS therapies with a better safety profile than dopaminergic antagonists.


Assuntos
Comportamento Animal , Receptores de GABA-A/metabolismo , Síndrome de Tourette/genética , Síndrome de Tourette/imunologia , Animais , Benzazepinas/farmacologia , Piscadela , Cataplexia , Modelos Animais de Doenças , Dopamina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Córtex Pré-Frontal/metabolismo , Reflexo de Sobressalto , Tiques/complicações
10.
J Anxiety Disord ; 78: 102361, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33508747

RESUMO

Recent meta-analyses indicated differences in fear acquisition and extinction between patients with anxiety-related disorders and comparison subjects. However, these effects are small and may hold for only a subsample of patients. To investigate individual trajectories in fear acquisition and extinction across patients with anxiety-related disorders (N = 104; before treatment) and comparison subjects (N = 93), data from a previous study (Duits et al., 2017) were re-analyzed using data-driven latent class growth analyses. In this explorative study, subjective fear ratings, shock expectancy ratings and startle responses were used as outcome measures. Fear and expectancy ratings, but not startle data, yielded distinct fear conditioning trajectories across participants. Patients were, compared to controls, overrepresented in two distinct dysfunctional fear conditioning trajectories: impaired safety learning and poor fear extinction to danger cues. The profiling of individual patterns allowed to determine that whereas a subset of patients showed trajectories of dysfunctional fear conditioning, a significant proportion of patients (≥50 %) did not. The strength of trajectory analyses as opposed to group analyses is that it allows the identification of individuals with dysfunctional fear conditioning. Results suggested that dysfunctional fear learning may also be associated with poor treatment outcome, but further research in larger samples is needed to address this question.


Assuntos
Extinção Psicológica , Medo , Ansiedade , Transtornos de Ansiedade , Condicionamento Clássico , Humanos , Reflexo de Sobressalto
11.
Schizophr Res ; 228: 118-123, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33434725

RESUMO

BACKGROUND: Impaired sensorimotor gating, commonly measured as disrupted prepulse inhibition (PPI) of the acoustic startle response, has been widely observed in psychotic diseases. However, most PPI studies published so far involve patients with long illness duration and different drug treatments. Few studies have investigated untreated patients at their first episode of psychotic symptoms. METHOD: PPI is an acoustic startle paradigm (30, 60-, 120-ms interstimulus intervals). Startle reactivity and habituation were succesfully assessed in 49 antipsychotic-naïve first-episode psychosis (FEP) patients and compared with 35 age- and gender-matched healthy control subjects. Mean age of patients was 28 years and 27 for controls. Patients treated with antipsychotics more than 30 days were not included in the study and twenty-three out of forty-nine patients received antipsychotic treatment with a mean treatment time of 13 days. RESULTS: PPI was significantly lower in FEP patients, compared to healthy controls. The PPI deficiency found in these patients was not due to antipsychotic treatment since PPI did not differ between treated (n=23) and untreated patients n=(26). By using the latent curve modeling we identified a delayed habituation in patients treated with antipsychotics, suggesting that antipsychotic treatment should be considered as a confound when investigating habituation in schizophrenia. CONCLUSIONS: Our results suggest that acute pharmacological treatment does not normalize PPI in FEP patients but should be considered as a confound when investigating habituation in these patients.


Assuntos
Antipsicóticos , Transtornos Psicóticos , Estimulação Acústica , Adulto , Antipsicóticos/uso terapêutico , Habituação Psicofisiológica , Humanos , Transtornos Psicóticos/tratamento farmacológico , Reflexo de Sobressalto , Filtro Sensorial
12.
J Neuroeng Rehabil ; 18(1): 5, 2021 01 07.
Artigo em Inglês | MEDLINE | ID: mdl-33413441

RESUMO

BACKGROUND: Impaired movement preparation of both anticipatory postural adjustments and goal directed movement as shown by a marked reduction in the incidence of StartReact responses during a standing reaching task was reported in individuals with stroke. We tested how transcranial direct current stimulation (tDCS) applied over the region of premotor areas (PMAs) and primary motor area (M1) affect movement planning and preparation of a standing reaching task in individuals with stroke. METHODS: Each subject performed two sessions of tDCS over the lesioned hemisphere on two different days: cathodal tDCS over PMAs and anodal tDCS over M1. Movement planning and preparation of anticipatory postural adjustment-reach sequence was examined by startReact responses elicited by a loud acoustic stimulus of 123 dB. Kinetic, kinematic, and electromyography data were recorded to characterize anticipatory postural adjustment-reach movement response. RESULTS: Anodal tDCS over M1 led to significant increase of startReact responses incidence at loud acoustic stimulus time point - 500 ms. Increased trunk involvement during movement execution was found after anodal M1 stimulation compared to PMAs stimulation. CONCLUSIONS: The findings provide novel evidence that impairments in movement planning and preparation as measured by startReact responses for a standing reaching task can be mitigated in individuals with stroke by the application of anodal tDCS over lesioned M1 but not cathodal tDCS over PMAs. This is the first study to show that stroke-related deficits in movement planning and preparation can be improved by application of anodal tDCS over lesioned M1. Trial registration ClinicalTrial.gov, NCT04308629, Registered 16 March 2020-Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/NCT04308629.


Assuntos
Córtex Motor/fisiopatologia , Reflexo de Sobressalto/fisiologia , Reabilitação do Acidente Vascular Cerebral/métodos , Acidente Vascular Cerebral/fisiopatologia , Estimulação Transcraniana por Corrente Contínua/métodos , Estimulação Acústica , Adulto , Fenômenos Biomecânicos , Feminino , Humanos , Masculino , Movimento , Posição Ortostática
13.
Exp Brain Res ; 239(3): 745-753, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33392695

RESUMO

When movements of individuals with stroke (iwS) are elicited by startling acoustic stimulus (SAS), reaching movements are faster, further, and directed away from the body. However, these startle-evoked movements also elicit task-inappropriate flexor activity, raising concerns that chronic exposure to startle might also induce heightened flexor activity during voluntarily elicited movement. The objective of this study is to evaluate the impact of startle exposure on voluntary movements during point-to-point reaching in individuals with moderate and severe stroke. We hypothesize that startle exposure will increase task-inappropriate activity in flexor muscles, which will be associated with worse voluntarily initiated reaching performance (e.g. decreased distance, displacement, and final accuracy). Eleven individuals with moderate-to-severe stroke (UEFM = 8-41/66 and MAS = 0-4/4) performed voluntary point-to-point reaching with 1/3 of trials elicited by an SAS. We used electromyography to measure activity in brachioradialis (BR), biceps (BIC), triceps lateral head (TRI), pectoralis (PEC), anterior deltoid (AD), and posterior deltoid (PD). Conversely to our hypothesis, exposure to startle did not increase abnormal flexion but rather antagonist activity in the elbow flexors and shoulder horizontal adductors decreased, suggesting that abnormal flexor/extensor co-contraction was reduced. This reduction of flexion led to increased reaching distance (18.2% farther), movement onset (8.6% faster), and final accuracy (16.1% more accurate) by the end of the session. This study offers the first evidence that exposure to startle in iwS does not negatively impact voluntary movement; moreover, exposure may improve volitionally activated reaching movements by decreasing abnormal flexion activity.


Assuntos
Braço , Acidente Vascular Cerebral , Adulto , Idoso , Cotovelo , Eletromiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Movimento , Músculo Esquelético , Reflexo de Sobressalto , Adulto Jovem
14.
Subst Use Misuse ; 56(1): 162-168, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33222602

RESUMO

BACKGROUND: Sexual minorities (e.g. lesbian, gay, bisexual) are at increased risk for alcohol use disorder (AUD) compared to heterosexuals. The minority stress model postulates that disparities in AUD stem, in part, from stress specific to sexual minorities (e.g. heterosexism). However, little research has examined psychophysiological markers of minority stress reactivity and how psychophysiological stress reactivity is associated with lifetime minority stress and alcohol use among sexual minorities. Emotion modulation of the startle response is a well-established paradigm for capturing psychophysiological stress reactivity under controlled laboratory conditions. Purpose: This preliminary study is the first to use the startle experimental paradigm to examine psychophysiological reactivity to stigma among sexual minorities. Procedures: Sexual minority participants (N = 20; 55% female), aged 18 to 27 years (M = 21.80, SD = 2.65), were recruited from the community. We compared startle reactivity in response to three types of stimuli (stigma, negative, and neutral) among heavy drinking sexual minority young adults. Although statistically underpowered, we also explored the associations between startle reactivity and self-reported drinking behaviors and lifetime minority stress. Results: Both stigma and general unpleasant stimuli produced more psychophysiological stress reactivity than neutral stimuli among sexual minorities. Psychophysiological stress reactivity was correlated with greater quantity of drinks reported on drinking days in the past month, but not greater frequency. Additionally, lifetime exposure to minority stress was associated with a blunted reactivity to stigma stimuli. Conclusions: These findings provide methodological advances and important implications for minority stress theory and alcohol use among sexual minorities.


Assuntos
Reflexo de Sobressalto , Minorias Sexuais e de Gênero , Consumo de Bebidas Alcoólicas , Bissexualidade , Feminino , Heterossexualidade , Humanos , Masculino , Adulto Jovem
15.
Dev Sci ; 24(1): e13000, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32497415

RESUMO

Risk for adverse outcomes, including the onset of mental illness, increases during adolescence. This increase may be linked to both new exposures, such as violence at home or in the community, or to physiological changes driven by puberty. There are significant sex differences in adolescent risk, for instance, anxiety disorders are significantly more prevalent in girls than boys. Fear learning is linked to mental health and may develop during adolescence, but the role of puberty in adolescent-specific change has not yet been systematically evaluated. We conducted a longitudinal study of fear learning that tested fear-potentiated startle (FPS) in 78 children (40 girls) aged 8-16 years. Participants completed two to three visits that included a differential fear conditioning task and self-report of both pubertal status and violence exposure. We tested for effects of sex, pubertal status, and violence exposure on FPS over time with latent growth curve models. We also examined the association between FPS and later anxiety symptoms. We found significant changes in FPS to the threat cue, but not the safety cue, across visits. Higher pubertal status was significantly associated with increased FPS to threat cues at each visit, whereas sex and violence exposure were not. FPS to threat during the baseline visit also predicted later anxiety symptoms. These findings suggest that puberty drives increased fear response to threat cues similarly for girls and boys, and that this effect may not be significantly impacted by individual differences in violence exposure during early adolescence.


Assuntos
Medo , Reflexo de Sobressalto , Adolescente , Ansiedade , Criança , Feminino , Humanos , Estudos Longitudinais , Masculino , Puberdade
16.
Eur J Pharmacol ; 891: 173685, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33127363

RESUMO

α7 nicotinic acetylcholine receptor (α7 nAChR) is an extensively validated target for several neurological and psychiatric conditions namely, dementia and schizophrenia, owing to its vital roles in cognition and sensorimotor gating. Positive allosteric modulation (PAM) of α7 nAChR represents an innovative approach to amplify endogenous cholinergic signaling in a temporally restricted manner in learning and memory centers of brain. α7 nAChR PAMs are anticipated to side-step burgeoning issues observed with several clinical-stage orthosteric α7 nAChR agonists, related to selectivity, tolerance/tachyphylaxis, thus providing a novel dimension in therapeutic strategy and pharmacology of α7 nAChR ion-channel. Here we describe a novel α7 nAChR PAM, LL-00066471, which potently amplified agonist-induced Ca2+ fluxes in neuronal IMR-32 neuroblastoma cells in a α-bungarotoxin (α-BTX) sensitive manner. LL-00066471 showed excellent oral bioavailability across species (mouse, rat and dog), low clearance and good brain penetration (B/P ratio > 1). In vivo, LL-00066471 robustly attenuated cognitive deficits in both procognitive and antiamnesic paradigms of short-term episodic and recognition memory in novel object recognition task (NORT) and social recognition task (SRT), respectively. Additionally, LL-00066471 mitigated apomorphine-induced sensorimotor gating deficits in acoustic startle reflex (ASR) and enhanced antipsychotic efficacy of olanzapine in conditioned avoidance response (CAR) task. Further, LL-00066471 corrected redox-imbalances and reduced cortico-striatal infarcts in stroke model. These finding together suggest that LL-00066471 has potential to symptomatically alleviate cognitive deficits associated with dementias, attenuate sensorimotor gating deficits in schizophrenia and correct redox-imbalances in cerebrovascular disorders. Therefore, LL-00066471 presents potential for management of cognitive impairments associated with neurological and psychiatric conditions.


Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Colinérgicos/farmacologia , Cognição/efeitos dos fármacos , Disfunção Cognitiva/prevenção & controle , Transtornos Neurológicos da Marcha/prevenção & controle , Filtro Sensorial/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Linhagem Celular Tumoral , Colinérgicos/farmacocinética , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Modelos Animais de Doenças , Cães , Comportamento Exploratório/efeitos dos fármacos , Transtornos Neurológicos da Marcha/metabolismo , Transtornos Neurológicos da Marcha/fisiopatologia , Transtornos Neurológicos da Marcha/psicologia , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/metabolismo , AVC Isquêmico/fisiopatologia , Masculino , Camundongos Endogâmicos BALB C , Teste de Campo Aberto/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Ratos Wistar , Reflexo de Sobressalto/efeitos dos fármacos , Transdução de Sinais , Comportamento Social , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
17.
Psychopharmacology (Berl) ; 238(4): 1047-1057, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33349900

RESUMO

RATIONALE: Calcineurin is a protein regulating cytokine expression in T lymphocytes and calcineurin inhibitors such as cyclosporine A (CsA) are widely used for immunosuppressive therapy. It also plays a functional role in distinct neuronal processes in the central nervous system. Disturbed information processing as seen in neuropsychiatric disorders is reflected by deficient sensorimotor gating, assessed as prepulse inhibition (PPI) of the acoustic startle response (ASR). OBJECTIVE: Patients who require treatment with immunosuppressive drugs frequently display neuropsychiatric alterations during treatment with calcineurin inhibitors. Importantly, knockout of calcineurin in the forebrain of mice is associated with cognitive impairments and symptoms of schizophrenia-like psychosis as seen after treatment with stimulants. METHODS: The present study investigated in rats effects of systemic acute and subchronic administration of CsA on sensorimotor gating. Following a single injection with effective doses of CsA, adult healthy male Dark Agouti rats were tested for PPI. For subchronic treatment, rats were injected daily with the same doses of CsA for 1 week before PPI was assessed. Since calcineurin works as a modulator of the dopamine pathway, activity of the enzyme tyrosine hydroxylase was measured in the prefrontal cortex and striatum after accomplishment of the study. RESULTS: Acute and subchronic treatment with the calcineurin inhibitor CsA disrupted PPI at a dose of 20 mg/kg. Concomitantly, following acute CsA treatment, tyrosine hydroxylase activity was reduced in the prefrontal cortex, which suggests that dopamine synthesis was downregulated, potentially reflecting a stimulatory impact of CsA on this neurotransmitter system. CONCLUSIONS: The results support experimental and clinical evidence linking impaired calcineurin signaling in the central nervous system to the pathophysiology of neuropsychiatric symptoms. Moreover, these findings suggest that therapy with calcineurin inhibitors may be a risk factor for developing neurobehavioral alterations as observed after the abuse of psychomotor stimulant drugs.


Assuntos
Inibidores de Calcineurina/farmacologia , Ciclosporina/farmacologia , Imunossupressores/farmacologia , Filtro Sensorial/efeitos dos fármacos , Animais , Dopamina/biossíntese , Masculino , Neostriado/enzimologia , Córtex Pré-Frontal/enzimologia , Ratos , Ratos Sprague-Dawley , Reflexo de Sobressalto/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismo
18.
Neurosci Lett ; 740: 135469, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33152455

RESUMO

Heterogeneous nuclear ribonuclear protein l-like (hnRNPLL) is an RNA binding protein that regulates alternative splicing of mRNA and is abundantly expressed in memory T lymphocytes of the immune system and in the brain. A hypomorphic allele of the gene encoding hnRNPLL (Hnrpllthunder) selectively reduces T cell accumulation in lymphoid tissues, but little is known about its effects in the brain. Therefore, we exposed Hnrpllthunder mice to a test battery with relevance for a range of psychiatric illnesses. Thunder mice showed enhanced immobility in the tail-suspension test for depression-related behaviours, impaired short-term spatial memory in the Y-maze and reduced avoidance learning in the active avoidance test. Thus, in addition to its reported effects on immune function, the hnRNPLL mutation in thunder mice selectively affected aspects of behaviour.


Assuntos
Ribonucleoproteínas Nucleares Heterogêneas/genética , Mutação/genética , Linfócitos T/imunologia , Alelos , Processamento Alternativo , Animais , Ansiedade/psicologia , Aprendizagem da Esquiva , Depressão/psicologia , Comportamento Exploratório , Feminino , Elevação dos Membros Posteriores/psicologia , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes Neurológicos , Reflexo de Sobressalto/genética , Memória Espacial
19.
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
20.
Autism Res ; 14(3): 450-463, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33372389

RESUMO

Atypical responses to fearful stimuli and the presence of various forms of anxiety are commonly seen in children with autism spectrum disorder (ASD). The fear potentiated startle paradigm (FPS), which has been studied both in relation to anxiety and as a probe for amygdala function, was carried out in 97 children aged 9-14 years including 48 (12 female) with ASD and 49 (14 female) with typical development (TD). In addition, exploratory analyses were conducted examining the association between FPS and amygdala volume as assessed with magnetic resonance imaging in a subset of the children with ASD with or without an anxiety disorder with available MRI data. While the startle latency was increased in the children with ASD, there was no group difference in FPS. FPS was not significantly associated with traditional Diagnostic and Statistical Manual (DSM) or "autism distinct" forms of anxiety. Within the autism group, FPS was negatively correlated with amygdala volume. Multiple regression analyses revealed that the association between FPS and anxiety severity was significantly moderated by the size of the amygdala, such that the association between FPS and anxiety was significantly more positive in children with larger amygdalas than smaller amygdalas. These findings highlight the heterogeneity of emotional reactivity associated with ASD and the difficulties in establishing biologically meaningful probes of altered brain function. LAY SUMMARY: Many children with autism spectrum disorder (ASD) have additional problems such as anxiety that can greatly impact their lives. How these co-occurring symptoms develop is not well understood. We studied the amygdala, a region of the brain critical for processing fear and a laboratory method called fear potentiated startle for measuring fear conditioning, in children with ASD (with and without an anxiety disorder) and typically developing children. Results showed that the connection between fear conditioning and anxiety is dependent on the size of the amygdala in children with ASD.


Assuntos
Tonsila do Cerebelo/diagnóstico por imagem , Ansiedade , Transtorno do Espectro Autista , Medo , Reflexo de Sobressalto , Adolescente , Ansiedade/complicações , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/diagnóstico por imagem , Criança , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino
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