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1.
Proc Natl Acad Sci U S A ; 121(19): e2307156121, 2024 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-38683996

RESUMEN

Tourette disorder (TD) is poorly understood, despite affecting 1/160 children. A lack of animal models possessing construct, face, and predictive validity hinders progress in the field. We used CRISPR/Cas9 genome editing to generate mice with mutations orthologous to human de novo variants in two high-confidence Tourette genes, CELSR3 and WWC1. Mice with human mutations in Celsr3 and Wwc1 exhibit cognitive and/or sensorimotor behavioral phenotypes consistent with TD. Sensorimotor gating deficits, as measured by acoustic prepulse inhibition, occur in both male and female Celsr3 TD models. Wwc1 mice show reduced prepulse inhibition only in females. Repetitive motor behaviors, common to Celsr3 mice and more pronounced in females, include vertical rearing and grooming. Sensorimotor gating deficits and rearing are attenuated by aripiprazole, a partial agonist at dopamine type II receptors. Unsupervised machine learning reveals numerous changes to spontaneous motor behavior and less predictable patterns of movement. Continuous fixed-ratio reinforcement shows that Celsr3 TD mice have enhanced motor responding and reward learning. Electrically evoked striatal dopamine release, tested in one model, is greater. Brain development is otherwise grossly normal without signs of striatal interneuron loss. Altogether, mice expressing human mutations in high-confidence TD genes exhibit face and predictive validity. Reduced prepulse inhibition and repetitive motor behaviors are core behavioral phenotypes and are responsive to aripiprazole. Enhanced reward learning and motor responding occur alongside greater evoked dopamine release. Phenotypes can also vary by sex and show stronger affection in females, an unexpected finding considering males are more frequently affected in TD.


Asunto(s)
Dopamina , Mutación , Síndrome de Tourette , Animales , Síndrome de Tourette/genética , Síndrome de Tourette/fisiopatología , Síndrome de Tourette/metabolismo , Ratones , Femenino , Masculino , Humanos , Dopamina/metabolismo , Recompensa , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Aprendizaje/fisiología , Conducta Animal , Inhibición Prepulso/genética , Filtrado Sensorial/genética
2.
Behav Pharmacol ; 35(4): 193-200, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38567425

RESUMEN

Prepulse inhibition (PPI) is a crucial indicator of sensorimotor gating that is often impaired in neuropsychiatric diseases. Although dopamine D1 receptor agonists have been found to disrupt PPI in mice, the underlying mechanisms are not fully understood. In this study, we aimed to identify the brain regions responsible for the PPI-disruptive effect of the D1 agonist in mice. Results demonstrated that intraperitoneal administration of the selective dopamine D1 receptor agonist SKF82958 dramatically inhibited PPI, while the dopamine D1 receptor antagonist SCH23390 enhanced PPI. Additionally, local infusion of SKF82958 into the nucleus accumbens and medial prefrontal cortex disrupted PPI, but not in the ventral hippocampus. Infusion of SCH23390 into these brain regions also failed to enhance PPI. Overall, the study suggests that the nucleus accumbens and medial prefrontal cortex are responsible for the PPI-disruptive effect of dopamine D1 receptor agonists. These findings provide essential insights into the cellular and neural circuit mechanisms underlying the disruptive effects of dopamine D1 receptor agonists on PPI and may contribute to the development of novel treatments for neuropsychiatric diseases.


Asunto(s)
Benzazepinas , Agonistas de Dopamina , Ratones Endogámicos C57BL , Núcleo Accumbens , Corteza Prefrontal , Inhibición Prepulso , Receptores de Dopamina D1 , Animales , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Agonistas de Dopamina/farmacología , Ratones , Benzazepinas/farmacología , Masculino , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/metabolismo , Inhibición Prepulso/efectos de los fármacos , Inhibición Prepulso/fisiología , Reflejo de Sobresalto/efectos de los fármacos , Filtrado Sensorial/efectos de los fármacos , Antagonistas de Dopamina/farmacología
3.
Physiol Behav ; 278: 114526, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38531426

RESUMEN

BACKGROUND: The utilization of methylphenidate (MPH) is experiencing a notable surge within the adult population. This growth can be attributed to two key factors: its recreational and cognitive enhancement purposes, as well as the rising prevalence of ADHD diagnoses within this population. This study examined acute and chronic oral MPH effects on attention in male and female Wistar rats. To this end, we used a prepulse inhibition (PPI) task, which is widely used to assess psychoactive drug effects in both humans and rodents. This task allowed us to evaluate changes in attention by analyzing sensorimotor gating associated with stimulus selection process. METHODS: Animals were administered a clinically relevant dose of MPH (5 mg/kg) daily for seven days. The estrous cycle phases of the female rats were measured during behavioral sessions. The PPI task was conducted 20 min after drug administration on day 1 (acute), day 7 (chronic), and 48 h post-treatment. RESULTS: Results indicated that both acute and chronic MPH treatment impaired PPI expression in male rats, but not in female rats, regardless of their estrous cycle phase. Furthermore, a differential effect of chronic MPH treatment on the PPI task was found in male rats. Specifically, on the seventh treatment day, the PPI effect was observed when animals undertook the PPI task for the first time but was impaired in those animals in which the initial PPI session occurred under the acute influence of the drug (day 1). CONCLUSIONS: These findings suggest that the impact of MPH on sensorimotor gating responses may vary based on sex and task experience, possibly leading to state-dependent effects in healthy individuals.


Asunto(s)
Estimulantes del Sistema Nervioso Central , Metilfenidato , Humanos , Femenino , Masculino , Ratas , Animales , Metilfenidato/farmacología , Ratas Wistar , Estimulantes del Sistema Nervioso Central/farmacología , Inhibición Prepulso , Caracteres Sexuales
4.
Psychophysiology ; 61(5): e14508, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38164815

RESUMEN

In emergency medical services, paramedics are informed of an emergency call by a high-intensity acoustic alarm called the "call alert." Sudden, loud sounds like the call alert may cause a startle response and be experienced as aversive. Studies have identified an association between the call alert and adverse health effects in first responders; conceivably, these adverse health effects might be reduced by modifying the call alert to blunt its startling and aversive properties. Here, we assessed whether the call alert causes a startle response and whether its startling and aversive properties are reduced when the call alert is preceded by a weak acoustic "prepulse," a process referred to as "prepulse inhibition" (PPI). Paramedics (n = 50; 34M:13F:3 not reported; ages 20-68) were exposed to four call alerts (two with and two without a prepulse) in counterbalanced order. Responses were measured using electromyography (measuring blink amplitude), visual analog scales (quantifying perceived call alert intensity and aversiveness), and an electrocardiogram (assessing heart rate). Paramedics responded to the call alert with a startle reflex blink and an increased heart rate. Acoustic prepulses significantly reduced the amplitude of the call alert-induced startle blink, the perceived sound intensity, and the perceived "dislike" of the call alert. These findings confirm that the call alert is associated with an acoustic startle response in paramedics; adding a prepulse to the call alert can reduce its startling and aversive properties. Conceivably, such reductions might also diminish adverse health effects associated with the call alert in first responders.


Asunto(s)
Servicios Médicos de Urgencia , Inhibición Prepulso , Humanos , Reflejo de Sobresalto/fisiología , Estimulación Acústica , Electromiografía
5.
J Psychiatry Neurosci ; 49(1): E1-E10, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38238035

RESUMEN

BACKGROUND: Deficits in prepulse inhibition may be a common feature in first-episode schizophrenia, bipolar disorder (BD) and major depressive disorder (MDD). We sought to explore the levels and viability of prepulse inhibition to differentiate first-episode schizophrenia, BD and MDD in patient populations. METHODS: We tested patients with first-episode schizophrenia, BD or MDD and healthy controls using prepulse inhibition paradigms, namely perceived spatial co-location (PSC-PPI) and perceived spatial separation (PSS-PPI). RESULTS: We included 53 patients with first-episode schizophrenia, 30 with BD and 25 with MDD, as well as 82 healthy controls. The PSS-PPI indicated that the levels of prepulse inhibition were smallest to largest, respectively, in the first-episode schizophrenia, BD, MDD and control groups. Relative to the healthy controls, the prepulse inhibition deficits in the first-episode schizophrenia group were significant (p < 0.001), but the prepulse inhibitions were similar between patients with BD and healthy controls, and between patients with MDD and healthy controls. The receiver operating characteristic curve analysis showed that PSS-PPI (area under the curve [AUC] 0.73, p < 0.001) and latency (AUC 0.72, p < 0.001) were significant for differentiating patients with first-episode schizophrenia or BD from healthy controls. LIMITATIONS: The demographics of the 4 groups were not ideally matched. We did not perform cognitive assessments. The possible confounding effect of medications on prepulse inhibition could not be eliminated. CONCLUSION: The level of prepulse inhibition among patients with first-episode schizophrenia was the lowest, with levels among patients with BD, patients with MDD and healthy controls increasingly higher. The PSS-PPI paradigm was more effective than PSC-PPI to recognize deficits in prepulse inhibition. These results provide a basis for further research on biological indicators that can assist differential diagnoses in psychosis.


Asunto(s)
Trastorno Bipolar , Trastorno Depresivo Mayor , Esquizofrenia , Humanos , Inhibición Prepulso/fisiología , Trastorno Bipolar/psicología , Estudios de Casos y Controles
6.
Behav Brain Res ; 459: 114762, 2024 02 29.
Artículo en Inglés | MEDLINE | ID: mdl-37977340

RESUMEN

The Roman high- (RHA) and low-avoidance (RLA) rats were bidirectionally selected and bred for, respectively, their rapid vs. extremely poor acquisition in the two-way active avoidance task. Consistent between-strain neurobehavioural differences have been found in anxiety- and stress-linked traits, as well as in schizophrenia-related phenotypes. RLAs display enhanced anxious- and stress-related phenotypes, whereas RHA rats show impulsivity, hyperactivity and attention/cognition-related impairments. Many of these typical behavioural phenotypes have been reported to be positively modulated by environmental treatments such as neonatal handling (NH). However, most studies on the Roman rat strains have been carried out in males. Thus, the present study for the first time focused on the joint evaluation of differences in novel object exploration (NOE), social interaction (SI), prepulse inhibition of the startle response (PPI), and cognitive performance and flexibility in various spatial tasks (using the Morris water maze, MWM) in females of both Roman rat strains. We also aimed at evaluating the long-lasting effects of NH treatment on the RHA vs. RLA profiles in these tests/tasks. Results show that anxiety-related behavior, as measured by the NOE test and self-grooming in the SI test, was increased in RLA rats, and dramatically reduced by NH. In the SI test RLA rats displayed diminished social interaction, which was rescued by NH. RHA females exhibited a deficit of PPI, which was not affected by NH. Spatial tasks in the MWM showed impairments of working memory, reference learning/memory and spatial reversal learning (i.e., cognitive flexibility) in RHA females. Spatial reference learning and cognitive flexibility (i.e., reversal task) showed some improvement in rats (mainly in RHAs) that had received NH during the first three weeks of life. With the exception of the SI test, the pattern of differences between female RHA vs. RLA profiles was overall consistent with what has previously been found in males of both strains, and NH treatment was able to enduringly improve some emotion-related and (spatial) cognitive outcomes in both strains.


Asunto(s)
Esquizofrenia , Femenino , Masculino , Ratas , Animales , Inhibición Prepulso/fisiología , Reflejo de Sobresalto , Cognición/fisiología , Atención , Reacción de Prevención/fisiología
7.
Mol Neurobiol ; 61(2): 622-634, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37650965

RESUMEN

Numerous pathogenic variants of SCN2A gene, encoding voltage-gated sodium channel α2 subunit Nav1.2 protein, have been identified in a wide spectrum of neuropsychiatric disorders including schizophrenia. However, pathological mechanisms for the schizophrenia-relevant behavioral abnormalities caused by the variants remain poorly understood. Here in this study, we characterized mouse lines with selective Scn2a deletion at schizophrenia-related brain regions, medial prefrontal cortex (mPFC) or ventral tegmental area (VTA), obtained by injecting adeno-associated viruses (AAV) expressing Cre recombinase into homozygous Scn2a-floxed (Scn2afl/fl) mice, in which expression of the Scn2a was locally deleted in the presence of Cre recombinase. The mice lacking Scn2a in the mPFC exhibited a tendency for a reduction in prepulse inhibition (PPI) in acoustic startle response. Conversely, the mice lacking Scn2a in the VTA showed a significant increase in PPI. We also found that the mice lacking Scn2a in the mPFC displayed increased sociability, decreased locomotor activity, and increased anxiety-like behavior, while the mice lacking Scn2a in the VTA did not show any other abnormalities in these parameters except for vertical activity which is one of locomotor activities. These results suggest that Scn2a-deficiencies in mPFC and VTA are inversely relevant for the schizophrenic phenotypes in patients with SCN2A variants.


Asunto(s)
Inhibición Prepulso , Reflejo de Sobresalto , Ratones , Humanos , Animales , Área Tegmental Ventral/fisiología , Corteza Prefrontal/metabolismo , Acústica
8.
Artículo en Inglés | MEDLINE | ID: mdl-38103855

RESUMEN

Acute ketamine administration results in psychotic symptoms similar to those observed in schizophrenia and is regarded as a pharmacological model of schizophrenia. Accumulating evidence suggests that patients with schizophrenia show increased IL-6 levels in the blood and cerebrospinal fluid and that IL-6 levels are associated with the severity of psychotic symptoms. In the present study, we found that a single ketamine exposure led to increased expression of IL-6 and IL-6Rα, decreased dendritic spine density, increased expression and currents of T-type calcium channels, and increased neuron excitability in the hippocampal CA1 area 12 h after exposure. Acute ketamine administration also led to impaired prepulse inhibition (PPI) 12 h after administration. Additionally, we found that the expression of signaling molecules IKKα/ß, NF-κB, JAK2, and STAT3 was upregulated 12 h after a single ketamine injection. The decreases in dendritic spine density, the increases in calcium currents and neuron excitability, and the impairments in PPI were ameliorated by blocking IL-6 or IL-6Rα. Our findings show that blocking IL-6 or its receptor may protect hippocampal neurons from hyperexcitability, thereby ameliorating ketamine-induced psychotic effects. Our study provides additional evidence that targeting IL-6 and its receptor is a potential strategy for treating psychotic symptoms in acute ketamine-induced psychosis and schizophrenia.


Asunto(s)
Ketamina , Trastornos Psicóticos , Esquizofrenia , Humanos , Ketamina/farmacología , Ketamina/uso terapéutico , Inhibición Prepulso , Interleucina-6 , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo
9.
Methods Mol Biol ; 2746: 121-133, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38070085

RESUMEN

Prepulse inhibition (PPI) is a measure of sensorimotor gating which is widely used in rodents to study information processing and attention dysfunction. PPI is commonly measured in rats and mice using automated equipment. Here, we present details of a PPI testing protocol extensively used in previous studies. The protocol includes a set pulse-alone startle level and prepulse-pulse combinations with varying interval and intensity. Variations of this protocol can be used depending on the experimental aim or equipment and software version.


Asunto(s)
Inhibición Prepulso , Reflejo de Sobresalto , Ratas , Ratones , Animales , Inhibición Prepulso/fisiología , Reflejo de Sobresalto/fisiología , Roedores , Estimulación Acústica/métodos , Acústica
10.
Sci Rep ; 13(1): 22871, 2023 12 18.
Artículo en Inglés | MEDLINE | ID: mdl-38129487

RESUMEN

Tests of human brain circuit function typically require fixed equipment in lab environments. We have developed a smartphone-based platform for neurometric testing. This platform, which uses AI models like computer vision, is optimized for at-home use and produces reproducible, robust results on a battery of tests, including eyeblink conditioning, prepulse inhibition of acoustic startle response, and startle habituation. This approach provides a scalable, universal resource for quantitative assays of central nervous system function.


Asunto(s)
Reflejo de Sobresalto , Teléfono Inteligente , Humanos , Reflejo de Sobresalto/fisiología , Estimulación Acústica , Inhibición Prepulso , Habituación Psicofisiológica
11.
Biol Psychol ; 184: 108711, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37832864

RESUMEN

A weak stimulus presented immediately before a more intense one reduces both the N1-P2 cortical response and the perceived intensity of the intense stimulus. The former effect is referred to as cortical prepulse inhibition (PPI), the latter as prepulse inhibition of perceived stimulus intensity (PPIPSI). Both phenomena are used to study sensory gating in clinical and non-clinical populations, however little is known about their relationship. Here, we investigated 1) the possibility that cortical PPI and PPIPSI are associated, and 2) how they are affected by attentional load. Participants were tasked with comparing the intensity of an electric pulse presented alone versus one preceded 200 ms by a weaker electric prepulse (Experiment 1), or an acoustic pulse presented alone with one preceded 170 ms by a weaker acoustic prepulse (Experiment 2). A counting task (easy vs. hard) manipulating attentional load was included in Experiment 2. In both experiments, we observed a relationship between N1-P2 amplitude and perceived intensity, where greater cortical PPI was associated with a higher probability of perceiving the 'pulse with prepulse' as less intense. Moreover, higher attentional load decreased observations of PPIPSI but had no effect on N1-P2 amplitude. Based on the findings we propose that PPIPSI partially relies on the allocation of attentional resources towards monitoring cortical channels that process stimulus intensity characteristics such as the N1-P2 complex.


Asunto(s)
Potenciales Evocados , Reflejo de Sobresalto , Humanos , Reflejo de Sobresalto/fisiología , Estimulación Acústica , Inhibición Prepulso/fisiología , Atención
12.
Transl Psychiatry ; 13(1): 321, 2023 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-37852987

RESUMEN

Many neurodevelopmental disorders, including autism spectrum disorder (ASD), are associated with changes in sensory processing and sensorimotor gating. The acoustic startle response and prepulse inhibition (PPI) of startle are widely used translational measures for assessing sensory processing and sensorimotor gating, respectively. The Cntnap2 knockout (KO) rat has proven to be a valid model for ASD, displaying core symptoms, including sensory processing perturbations. Here, we used a novel method to assess startle and PPI in Cntnap2 KO rats that allows for the identification of separate scaling components: startle scaling, which is a change in startle amplitude to a given sound, and sound scaling, which reflects a change in sound processing. Cntnap2 KO rats show increased startle due to both an increased overall response (startle scaling) and a left shift of the sound/response curve (sound scaling). In the presence of a prepulse, wildtype rats show a reduction of startle due to both startle scaling and sound scaling, whereas Cntnap2 KO rats show normal startle scaling, but disrupted sound scaling, resulting in the reported PPI deficit. These results validate that startle and sound scaling by a prepulse are indeed two independent processes, with only the latter being impaired in Cntnap2 KO rats. As startle scaling is likely related to motor output and sound scaling to sound processing, this novel approach reveals additional information on the possible cause of PPI disruptions in preclinical models.


Asunto(s)
Trastorno del Espectro Autista , Reflejo de Sobresalto , Animales , Ratas , Estimulación Acústica/métodos , Trastorno del Espectro Autista/genética , Inhibición Prepulso , Reflejo de Sobresalto/fisiología , Filtrado Sensorial
13.
Neuropharmacology ; 239: 109689, 2023 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-37597609

RESUMEN

Obsessive-compulsive disorder (OCD) is characterised by excessive intrusive thoughts that may cause an individual to engage in compulsive behaviours. Frontline pharmacological treatments (i.e., selective serotonin reuptake inhibitors (SSRIs)) leave approximately 40% of patients refractory to treatment. To investigate the possibility of novel pharmacological therapies for OCD, as well as the potential mechanisms underlying its pathology, we used the Sapap3 knockout (KO) mouse model of OCD, which exhibits increased anxiety and compulsive grooming behaviours. Firstly, we investigated whether administration of the NMDA receptor (NMDAR) antagonist ketamine (30 mg/kg), would reduce anxiety and grooming behaviour in Sapap3 KO mice. Anxiety-like behaviour was measured via time spent in the light component of the light-dark box test. Grooming behaviour was recorded and scored in freely moving mice. In line with previous works conducted in older animals (i.e. typically between 6 and 9 months of age), we confirmed here that Sapap3 KO mice exhibit an anxious, compulsive grooming, hypolocomotive and reduced body weight phenotype even at a younger age (i.e., 2-3 months of age). However, we found that acute administration of ketamine did not cause a reduction in anxiety or grooming behaviour. We then investigated in vivo glutamatergic function via the administration of a different NMDAR antagonist, MK-801 (0.25 mg/kg), prior to locomotion and prepulse inhibition assays. We found evidence of altered functional NMDAR activity, as well as sexually dimorphic prepulse inhibition, a measure of sensorimotor gating, in Sapap3 KO mice. These results are suggestive of in vivo glutamatergic dysfunction and their functional consequences, enabling future research to further investigate novel treatments for OCD.


Asunto(s)
Maleato de Dizocilpina , Ketamina , Animales , Ratones , Maleato de Dizocilpina/farmacología , Ketamina/farmacología , Receptores de N-Metil-D-Aspartato , Conducta Compulsiva , Inhibición Prepulso , Proteínas del Tejido Nervioso/genética
14.
Psychopharmacology (Berl) ; 240(9): 2005-2012, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37580441

RESUMEN

RATIONALE: Rodent vendors are often utilized interchangeably, assuming that the phenotype of a given strain remains standardized between colonies. Several studies, however, have found significant behavioral and physiological differences between Sprague Dawley (SD) rats from separate vendors. Prepulse inhibition of startle (PPI), a form of sensorimotor gating in which a low-intensity leading stimulus reduces the startle response to a subsequent stimulus, may also vary by vendor. Differences in PPI between rat strains are well known, but divergence between colonies within the SD strain lacks thorough examination. OBJECTIVES: We explored intrastrain variation in PPI by testing SD rats from two vendors: Envigo and Charles River (CR). METHODS: We selected drugs acting on four major neurotransmitter systems that have been repeatedly shown to modulate PPI: dopamine (apomorphine; 0.5, 1.5, 3.0 mg/kg), acetylcholine (scopolamine; 0.1, 0.5, 1.0 mg/kg), glutamate (dizocilpine; 0.5, 1.5, 2.5 mg/kg), and serotonin (2,5-Dimethoxy-4-iodoamphetamine, DOI; 0.25, 0.5, 1.0 mg/kg). We determined PPI and startle amplitude for each drug in male and female Envigo and CR SD rats. RESULTS: SD rats from Envigo showed dose-dependent decreases in PPI after apomorphine, scopolamine, or dizocilpine administration, without significant effects on startle amplitude. SD rats from CR were less sensitive to modulation of PPI and/or more sensitive to modulation of startle amplitude, across the three drugs. CONCLUSIONS: SD rats showed vendor differences in sensitivity to pharmacological modulation of PPI and startle. We encourage researchers to sample rats from separate vendors before experimentation to identify the most suited source of subjects for their specific endpoints.


Asunto(s)
Dopamina , Inhibición Prepulso , Ratas , Masculino , Femenino , Animales , Dopamina/farmacología , Ratas Sprague-Dawley , Apomorfina/farmacología , Agonistas de Dopamina/farmacología , Acetilcolina , Preparaciones Farmacéuticas , Ácido Glutámico , Maleato de Dizocilpina/farmacología , Reflejo de Sobresalto , Estimulación Acústica , Derivados de Escopolamina/farmacología
15.
BMC Psychol ; 11(1): 226, 2023 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-37550772

RESUMEN

BACKGROUND: Psychopathological research is moving from a specific approach towards transdiagnosis through the analysis of processes that appear transversally to multiple pathologies. A phenomenon disrupted in several disorders is prepulse inhibition (PPI) of the startle response, in which startle to an intense sensory stimulus, or pulse, is reduced if a weak stimulus, or prepulse, is previously presented. OBJECTIVE AND METHODS: The present systematic review analyzed the role of PPI deficit as a possible transdiagnostic process for four main groups of neuropsychiatric disorders: (1) trauma-, stress-, and anxiety-related disorders (2) mood-related disorders, (3) neurocognitive disorders, and (4) other disorders such as obsessive-compulsive, tic-related, and substance use disorders. We used Web of Science, PubMed and PsycInfo databases to search for experimental case-control articles that were analyzed both qualitatively and based on their potential risk of bias. A total of 64 studies were included in this systematic review. Protocol was submitted prospectively to PROSPERO 04/30/2022 (CRD42022322031). RESULTS AND CONCLUSION: The results showed a general PPI deficit in the diagnostic groups mentioned, with associated deficits in the dopaminergic neurotransmission system, several areas implied such as the medial prefrontal cortex or the amygdala, and related variables such as cognitive deficits and anxiety symptoms. It can be concluded that the PPI deficit appears across most of the neuropsychiatric disorders examined, and it could be considered as a relevant measure in translational research for the early detection of such disorders.


Asunto(s)
Trastornos del Conocimiento , Inhibición Prepulso , Humanos , Inhibición Prepulso/fisiología , Reflejo de Sobresalto/fisiología , Trastornos del Humor , Trastornos de Ansiedad/diagnóstico , Estimulación Acústica/métodos
16.
Methods Mol Biol ; 2687: 57-64, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37464162

RESUMEN

Prepulse inhibition of the startle response enables measuring animal behavior and helps us understand core aspects of neuropsychiatric diseases. Prepulse inhibition is considered a translational indicator of sensorimotor gating deficits present in schizophrenia patients and is crucial in the characterization of animal models of schizophrenia-like behaviors. Hallucinogenic drugs acting through 5-HT2A receptors, such as psilocybin, lysergic acid diethylamide (LSD), and dimethoxyiodoamphetamine (DOI), produce symptoms in healthy subjects comparable to those seen in schizophrenia and can be used in rodent models for mimicking some of these behaviors. Here we describe a protocol for the evaluation of prepulse inhibition of the startle response in CD1-Swiss male mice after a single dose of the hallucinogenic drug DOI.


Asunto(s)
Inhibición Prepulso , Esquizofrenia , Ratones , Masculino , Animales , Reflejo de Sobresalto/fisiología , Filtrado Sensorial
17.
Neuropsychopharmacol Rep ; 43(3): 365-372, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37280178

RESUMEN

AIM: Proinflammatory cytokines such as interleukin-6 (IL-6) and IL-17A have been implicated in the pathophysiology of schizophrenia which often shows sensorimotor gating abnormalities. This study aimed to examine whether a proinflammatory cytokine, IL-17A, induces impairment in sensorimotor gating in mice. We also examined whether IL-17A administration affects GSK3α/ß protein level or phosphorylation in the striatum. METHODS: Recombinant mouse IL-17A (low-dose: 0.5 ng/mL and high-dose: 50 ng/mL with 10 µL/g mouse body weight, respectively) or vehicle was intraperitoneally administered into C57BL/6 male mice 10 times in 3 weeks (sub-chronic administration). Prepulse inhibition test using acoustic startle stimulus was conducted 4 weeks after the final IL-17A administration. We evaluated the effect of IL-17A administration on protein level or phosphorylation of GSK3α/ß in the striatum by using Western blot analysis. RESULTS: Administration of IL-17A induced significant PPI deterioration. Low-dose of IL-17A administration significantly decreased both GSK3α (Ser21) and GSK3ß (Ser9) phosphorylation in mouse striatum. There was no significant alteration of GSK3α/ß protein levels except for GSK3α in low-dose IL-17A administration group. CONCLUSION: We demonstrated for the first time that sub-chronic IL-17A administration induced PPI disruption and that IL-17A administration resulted in decreased phosphorylation of GSKα/ß at the striatum. These results suggest that IL-17A could be a target molecule in the prevention and treatment of sensorimotor gating abnormalities observed in schizophrenia.


Asunto(s)
Inhibición Prepulso , Reflejo de Sobresalto , Ratones , Masculino , Animales , Reflejo de Sobresalto/fisiología , Interleucina-17 , Ratones Endogámicos C57BL , Acústica
18.
Behav Brain Res ; 451: 114519, 2023 08 05.
Artículo en Inglés | MEDLINE | ID: mdl-37263423

RESUMEN

Zika virus (ZIKV) infection causes severe neurological consequences in both gestationally-exposed infants and adults. Sensorial gating deficits strongly correlate to the motor, sensorial and cognitive impairments observed in ZIKV-infected patients. However, no startle response or prepulse inhibition (PPI) assessment has been made in patients or animal models. In this study, we identified different outcomes according to the age of infection and sex in mice: neonatally infected animals presented an increase in PPI and delayed startle latency. However, adult-infected male mice presented lower startle amplitude, while a PPI impairment was observed 14 days after infection in both sexes. Our data further the understanding of the functional impacts of ZIKV on the developing and mature nervous system, which could help explain other behavioral and cognitive alterations caused by the virus. With this study, we support the startle reflex testing in ZIKV-exposed patients, especially infants, allowing for early detection of functional neuromotor damage and early intervention.


Asunto(s)
Infección por el Virus Zika , Virus Zika , Femenino , Masculino , Animales , Ratones , Reflejo de Sobresalto/fisiología , Inhibición Prepulso , Infección por el Virus Zika/complicaciones , Estimulación Acústica
19.
Pharmacol Biochem Behav ; 229: 173593, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37390974

RESUMEN

RATIONALE: Maternal polyinosinic-polycytidylic acid (Poly I:C) exposure leads to an increase in various proinflammatory cytokines and causes schizophrenia-like symptoms in offspring. In recent years, group I metabotropic glutamate receptors (mGluRs) have emerged as a potential target in the pathophysiology of schizophrenia. OBJECTIVES: The aim of our study was to investigate the behavioral and molecular changes by using the mGlu1 receptor positive allosteric modulator (PAM) agent RO 67-7476, and the negative allosteric modulator (NAM) agent JNJ 16259685 and the mGlu5 receptor PAM agent VU-29, and NAM agent fenobam in the Poly I:C-induced schizophrenia model in rats. METHODS: Female Wistar albino rats were treated with Poly I:C on day 14 of gestation after mating. On the postnatal day (PND) 34-35, 56-57 and 83-84, behavioral tests were performed in the male offspring. On the PND84, brain tissue was collected and the level of proinflammatory cytokines was determined by ELISA method. RESULTS: Poly I:C caused impairments in all behavioral tests and increased the levels of proinflammatory cytokines. While PAM agents caused significant improvements in prepulse inhibition (PPI), novel object recognition (NOR), spontaneous alternation and reference memory tests, they brought the levels of proinflammatory cytokines closer to the control group. NAM agents were ineffective on behavioral tests. It was observed that PAM agents significantly improved Poly I:C-induced disruption in behavioral and molecular analyses. CONCLUSIONS: These results suggest that PAM agents, particularly the mGlu5 receptor VU-29, are also promising and could be a potential target in schizophrenia.


Asunto(s)
Esquizofrenia , Ratas , Animales , Masculino , Femenino , Ratas Wistar , Esquizofrenia/tratamiento farmacológico , Poli I-C/farmacología , Encéfalo , Inhibición Prepulso , Regulación Alostérica
20.
Neurotoxicol Teratol ; 98: 107180, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37160210

RESUMEN

Several studies have begun to demonstrate the possible cognitive and physiological benefits of a fortified vitamin D diet. However, the behavioral effects of a high vitamin D fortified diet during adolescence has not been fully explored. In the present study, a 4-week vitamin D fortified diet (20,000 IU/Kg) compared to controls (1500 IU/Kg) was administered during the juvenile (4 weeks old) or early adult period (8 weeks old) in C57BL/6 J mice to investigate the effects of fortification on cognition, behavior, and their bone phenotype. After 4 weeks on the diet, vitamin D-treated and control groups underwent a 4-week battery of behavioral tests while remaining on their respective diets. We found that a fortified diet affected behavior in both an age- and sex-specific manner. When vitamin D was administered to juveniles, both sexes displayed impaired habituation to a loud tone. However, females also presented with impaired prepulse inhibition compared to female controls. In the adult treated group, the fortified diet increased only time spent in the open field and had no effect on anxiety-like behavior in the elevated plus maze. Juvenile mice treated with a high vitamin D fortified diet showed a decrease in the total volume compared to the control group in the proximal metaphysis and midshaft region of their femur. There were no differences in bone measurements for mice treated during adulthood. Overall, our results suggest that the juvenile period is a more sensitive time point to the startle response and bone effects of a diet supplemented with high vitamin D, while adults exhibited alterations in locomotive behavior.


Asunto(s)
Inhibición Prepulso , Vitamina D , Masculino , Femenino , Ratones , Animales , Ratones Endogámicos C57BL , Vitamina D/farmacología , Reflejo de Sobresalto , Suplementos Dietéticos
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