RESUMEN
Pediatric gastroenterology patients are at risk for co-occurring behavioral health concerns, such as depression and anxiety, compared with youth without medical conditions. The objective of this systematic review was to assess the scientific literature supporting the hypothesis that integrating behavioral health services into gastroenterology clinics could improve patient psychosocial well-being. We searched MEDLINE, EMBASE, The Cochrane Library, Web of Science, PsycINFO, and CINAHL databases and gray literature to identify studies reporting the impact of behavioral health integration on the psychosocial well-being of pediatric gastroenterology patients. Two independent coders evaluated each study for inclusion and extracted data regarding patient demographics, study design, behavioral health integration approaches, and psychosocial outcomes. Results were synthesized using narrative review procedures. Eighteen studies met the inclusion criteria. Most reported outcomes from research grant-funded randomized controlled trials or open trials investigating behavioral health interventions based on Cognitive-Behavioral Therapy, primarily with youth with irritable bowel disease or functional gastrointestinal disorders. Within the highest-quality, comparable studies, nearly 80% reported at least one statistically significant treatment effect on patient psychosocial well-being. Many studies used rigorous methods that minimize bias, but did not provide models for sustainable, programmatic behavioral health integration outside the bounds of a research study. The studies included in this review suggest that behavioral integration could have the potential to positively impact gastroenterology patients' psychosocial functioning. However, more research is needed to investigate the appropriate intensity of behavioral health services and evaluate models for integrating behavioral healthcare in pediatric gastroenterology settings beyond the research-funded clinical trial context.
Asunto(s)
Terapia Cognitivo-Conductual , Niño , Adolescente , Humanos , Terapia Cognitivo-Conductual/métodos , Trastornos de Ansiedad , Ansiedad/terapia , Servicios de SaludRESUMEN
Numerous mental health disorders are characterized by cognitive impairments that result in poor vocational and social outcomes. Among the cognitive domains commonly affected, working memory deficits have been noted in patients with attention-deficit/hyperactivity disorder (Martinussen et al. in J Am Acad Child Adolesc Psychiatry 44:377-384, 2005), post-traumatic stress disorder (Honzel et al. in Cogn Affect Behav Neurosci 14:792-804, 2014), and consistently with schizophrenia patients (Callicott et al. in Cereb Cortex 10:1078-1092, 2000; Lewis et al. in Front Hum Neurosci 10:85, 2005; Amann et al. in Brain Res Bull 83:147-161, 2010; Limongi et al. in Schizophr Res 197:386-391, 2018). Oscillations in neural activity from electroencephalogram (EEG) recordings are decomposed by frequency, and band-specific decreases in gamma power (> 30 Hz) have been correlated with working memory ability. This study examined within-subject changes in power of frequency-specific bands during sample versus choice trials during a spatial working memory paradigm (T-maze). EEG was recorded using a relatively novel wireless EEG telemetry system fully implanted within the mouse, enabling uninhibited movement during behavioral tasks. No significant differences were found between sample and correct choice phases in the alpha, theta or gamma frequency ranges. Evoked power was significantly higher during the choice phase than the sample phase in the high-beta/low-gamma frequency range. This frequency range has been implicated in the propagation of cortical predictions to lower levels of stimuli encoding in a top-down hierarchical manner. Results suggest there is an increase in brain activity during correct trials when the mouse enters the opposite arm during the choice phase compared to the sample phase, likely due to prediction error resulting from a discrepancy between present and prior experience. Future studies should identify specific cortical networks involved and investigate neural activity at the neuronal level.
Asunto(s)
Ritmo beta/fisiología , Ritmo Gamma/fisiología , Aprendizaje por Laberinto/fisiología , Memoria a Corto Plazo/fisiología , Memoria Espacial/fisiología , Animales , Predicción , Ratones , Ratones Endogámicos C57BLRESUMEN
Schizophrenia is a disabling psychiatric disease characterized by symptoms including hallucinations, delusions, social withdrawal, loss of pleasure, and inappropriate affect. Although schizophrenia is marked by dysfunction in dopaminergic and glutamatergic signaling, it is not presently clear how these dysfunctions give rise to symptoms. The aberrant salience hypothesis of schizophrenia argues that abnormal attribution of motivational salience to stimuli is one of the main contributors to both positive and negative symptoms of schizophrenia. The proposed mechanisms for this hypothesis are overactive striatal dopaminergic and hypoactive glutamatergic signaling. The current study assessed salience attribution in mice (n = 72) using an oddball paradigm in which an infrequent stimulus either co-occurred with shock (conditioned group) or was presented alone (non-conditioned group). Behavioral response (freezing) and electroencephalogram (whole brain and amygdala) were used to assess salience attribution. Mice with pyramidal cell-selective knockout of ionotropic glutamate receptors (GluN1) were used to reproduce a prominent physiological change involved in schizophrenia. Non-conditioned knockout mice froze significantly more in response to the unpaired stimulus than non-conditioned wild-type mice, suggesting that this irrelevant cue acquired motivational salience for the knockouts. In accordance with this finding, low-frequency event-related spectral perturbation was significantly increased in non-conditioned knockout mice relative to both conditioned knockout and non-conditioned wild-type mice. These results suggest that pyramidal cell-selective GluN1 knockout leads to inappropriate attribution of salience for irrelevant stimuli as characterized by abnormalities in both behavior and brain circuitry functions.
Asunto(s)
Conducta Animal/fisiología , Encéfalo/fisiología , Condicionamiento Clásico/fisiología , Motivación/fisiología , Células Piramidales/fisiología , Esquizofrenia/fisiopatología , Amígdala del Cerebelo/fisiología , Animales , Modelos Animales de Enfermedad , Electroencefalografía , Miedo/fisiología , Reacción Cataléptica de Congelación/fisiología , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso , Receptores de N-Metil-D-AspartatoRESUMEN
The chromosome 15q13.3 microdeletion is a pathogenic copy number variation conferring epilepsy, intellectual disability, schizophrenia, and autism spectrum disorder (ASD). We generated mice carrying a deletion of 1.2 Mb homologous to the 15q13.3 microdeletion in human patients. Here, we report that mice with a heterozygous deletion on a C57BL/6 background (D/+ mice) demonstrated phenotypes including enlarged/heavier brains (macrocephaly) with enlarged lateral ventricles, decreased social interactions, increased repetitive grooming behavior, reduced ultrasonic vocalizations, decreased auditory-evoked gamma band EEG, and reduced event-related potentials. D/+ mice had normal body weight, activity levels, sensory gating, and cognitive abilities and no signs of epilepsy/seizures. Our results demonstrate that D/+ mice represent ASD-related phenotypes associated with 15q13.3 microdeletion syndrome. Further investigations using this chromosome-engineered mouse model may uncover the common mechanism(s) underlying ASD and other neurodevelopmental/psychiatric disorders representing the 15q13.3 microdeletion syndrome, including epilepsy, intellectual disability, and schizophrenia. SIGNIFICANCE STATEMENT: Recently discovered pathologic copy number variations (CNVs) from patients with neurodevelopmental/psychiatric disorders show very strong penetrance and thus are excellent candidates for mouse models of disease that can mirror the human genetic conditions with high fidelity. A 15q13.3 microdeletion in humans results in a range of neurodevelopmental/psychiatric disorders, including epilepsy, intellectual disability, schizophrenia, and autism spectrum disorder (ASD). The disorders conferred by a 15q13.3 microdeletion also have overlapping genetic architectures and comorbidity in other patient populations such as those with epilepsy and schizophrenia/psychosis, as well as schizophrenia and ASD. We generated mice carrying a deletion of 1.2 Mb homologous to the 15q13.3 microdeletion in human patients, which allowed us to investigate the potential causes of neurodevelopmental/psychiatric disorders associated with the CNV.
Asunto(s)
Trastorno del Espectro Autista/fisiopatología , Encéfalo/patología , Trastornos de los Cromosomas/fisiopatología , Discapacidad Intelectual/fisiopatología , Convulsiones/fisiopatología , Animales , Ansiedad/etiología , Aprendizaje por Asociación/fisiología , Encéfalo/metabolismo , Encéfalo/fisiopatología , Deleción Cromosómica , Trastornos de los Cromosomas/genética , Trastornos de los Cromosomas/patología , Cromosomas Humanos Par 15/genética , Discriminación en Psicología/efectos de los fármacos , Discriminación en Psicología/fisiología , Potenciales Evocados/fisiología , Femenino , Expresión Génica/fisiología , Aseo Animal/fisiología , Humanos , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Relaciones Interpersonales , Masculino , Memoria/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Pilocarpina/farmacología , Convulsiones/genética , Convulsiones/patología , Olfato/fisiología , Vocalización Animal/fisiologíaRESUMEN
Reductions in glutamate function are regarded as an important contributory factor in schizophrenia. However, there is a paucity of animal models characterized by developmental and sustained reductions in glutamate function. Pharmacological models using NMDA antagonists have been widely used but these typically produce only transient changes in behavior and brain function. Likewise, mice with homozygous constitutive reductions in glutamate receptor expression show stable brain and behavioral changes, but many of these phenotypes are more severe than the human disease. The current study examines a variety of schizophrenia-related EEG measures in mice with a heterozygous alteration of the NMDA receptor NR1 subunit gene (NR1) that is known to result in reduced NR1 receptor expression in the homozygous mouse (NR1-/-). (NR1+/-) mice showed a 30% reduction in NR1 receptor expression and were reared after weaning in either group or isolated conditions. Outcome measures include the response to paired white noise stimuli, escalating inter-stimulus intervals (ISIs) and deviance-related mismatch negativity (MMN). In contrast to what has been reported in (NR1-/-) mice and mice treated with NMDA antagonists, (NR1+/-) mice showed no change on obligatory Event Related Potential (ERP) measures including the murine P50 and N100 equivalents (P20 and N40), or measures of baseline or evoked gamma power. Alternatively, (NR1+/-) mice showed a marked reduction in response to a deviant auditory tone during MMN task. Data suggest that EEG response to deviant, rather than static, stimuli may be more sensitive for detecting subtle changes in glutamate function. Deficits in these heterozygous NR1 knockdown mice are consistent with data demonstrating MMN deficits among family members of schizophrenia patients and among prodromal patients. Therefore, the current study suggests that (NR1+/-) mice may be among the most sensitive models for increased vulnerability to schizophrenia.
Asunto(s)
Encéfalo/fisiopatología , Potenciales Evocados/fisiología , Ritmo Gamma/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/fisiopatología , Aislamiento Social , Animales , Modelos Animales de Enfermedad , Predisposición Genética a la Enfermedad , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Síntomas ProdrómicosRESUMEN
The complex and heterogeneous genetic architecture of schizophrenia inspires us to look beyond individual risk genes for therapeutic strategies and target their interactive dynamics and convergence. Postsynaptic NMDA receptor (NMDAR) complexes are a site of such convergence. Src kinase is a molecular hub of NMDAR function, and its protein interaction subnetwork is enriched for risk-genes and altered protein associations in schizophrenia. Previously, Src activity was found to be decreased in post-mortem studies of schizophrenia, contributing to NMDAR hypofunction. PSD-95 suppresses Src via interacting with its SH2 domain. Here, we devised a strategy to suppress the inhibition of Src by PSD-95 via employing a cell penetrating and Src activating PSD-95 inhibitory peptide (TAT-SAPIP). TAT-SAPIP selectively increased post-synaptic Src activity in humans and mice, and enhanced synaptic NMDAR currents in mice. Chronic ICV injection of TAT-SAPIP rescued deficits in trace fear conditioning in Src hypomorphic mice. We propose blockade of the Src-PSD-95 interaction as a proof of concept for the use of interfering peptides as a therapeutic strategy to reverse NMDAR hypofunction in schizophrenia and other illnesses.
RESUMEN
Ketamine is an NMDA receptor antagonist with psychotomimetic, dissociative, amnestic and euphoric effects. When chronically abused, ketamine users display deficits in cognition and information processing, even following long-term abstinence from the drug. While animal studies have shown evidence of behavioral changes and cognitive deficits that mimic those seen in humans within the period immediately following subchronic ketamine, a few animal studies have assessed long-term changes following cessation of ketamine exposure. To this end, the present study assessed event related potentials (ERPs) and EEG oscillations in mice exposed to subchronic ketamine following a 6month period of abstinence from the drug. Ketamine-treated mice showed no change in P20, but did show marked reductions in amplitude of the later N40 and P80 components, consistent with previous studies of acute ketamine exposure. Additionally, ketamine-treated animals showed a significant reduction in stimulus evoked theta oscillations. To assess the functional significance of these changes, mice were also assessed on a series of behavioral and cognitive tests, including progressive ratio (motivation), extinction (behavioral flexibility) and win-shift radial maze (spatial memory). Subchronic ketamine produced marked disruptions in reversal learning and spatial memory. Analysis of brains from ketamine-treated mice failed to show evidence of neuronal degeneration as determined by NueN immunohistochemistry, but did show increased astrocyte proliferation and decreased expression of the glial specific glutamate transporter, GLT-1. These results strongly suggest: 1) that subchronic ketamine induces significant changes in brain function that long exceed exposure to the drug; 2) that ketamine exposure in mice induces lasting cognitive impairments closely resembling those observed in human ketamine abusers; 3) that ERP and EEG measures are highly sensitive to alterations in brain function associated with reduced cognitive function; and 4) that the brain changes induced by chronic ketamine treatment are suggestive of long-term adaptive or plastic, rather than degenerative, changes.
Asunto(s)
Astrocitos/efectos de los fármacos , Encéfalo/efectos de los fármacos , Cognición/efectos de los fármacos , Electroencefalografía/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/toxicidad , Transportador 2 de Aminoácidos Excitadores/metabolismo , Ketamina/toxicidad , Estimulación Acústica , Animales , Astrocitos/metabolismo , Conducta Animal/efectos de los fármacos , Encéfalo/fisiopatología , Trastornos del Conocimiento/inducido químicamente , Condicionamiento Operante/efectos de los fármacos , Potenciales Evocados Auditivos/efectos de los fármacos , Transportador 2 de Aminoácidos Excitadores/genética , Extinción Psicológica/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismo , Ratones , Ratones Endogámicos C3H , Parvalbúminas/genética , Parvalbúminas/metabolismo , Fosfopiruvato Hidratasa/metabolismo , ARN Mensajero/metabolismo , Tiempo de Reacción/efectos de los fármacos , Esquema de RefuerzoRESUMEN
Cognitive deficit remains an intractable symptom of schizophrenia, accounting for substantial disability. Despite this, little is known about the cause of cognitive dysfunction in schizophrenia. Recent studies suggest that schizophrenia patients show several changes in dentate gyrus structure and functional characteristic of immaturity. The immature dentate gyrus (iDG) has been replicated in several mouse models, most notably the CaMKIIα heterozygous mouse (CaMKIIα-hKO). The current study characterizes behavioral phenotypes of CaMKIIα-hKO mice and determines their neurophysiological profile using electroencephalogram (EEG) recording from hippocampus. CaMKIIα-hKO mice were hypoactive in home-cage environment; however, they displayed less anxiety-like phenotype, suggestive of impulsivity-like behavior. In addition, severe cognitive dysfunction was evident in CaMKIIα-hKO mice as examined by novel object recognition and contextual fear conditioning. Several EEG phenomena established in both patients and relevant animal models indicate key pathological changes associated with the disease, include auditory event-related potentials and time-frequency EEG oscillations. CaMKIIα-hKO mice showed altered event-related potentials characterized by an increase in amplitude of the N40 and P80, as well as increased P80 latency. These mice also showed increased power in theta range time-frequency measures. Additionally, CaMKIIα-hKO mice showed spontaneous bursts of spike wave activity, possibly indicating absence seizures. The GABAB agonist baclofen increased, while the GABAB antagonist CGP35348 and the T-Type Ca2+ channel blocker Ethosuximide decreased spike wave burst frequency. None of these changes in event-related potentials or EEG oscillations are characteristic of those observed in general population of patients with schizophrenia; yet, CaMKIIα-hKO mice likely model a subpopulation of patients with schizophrenia.
Asunto(s)
Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Esquizofrenia , Animales , Calcio , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Modelos Animales de Enfermedad , Electroencefalografía , Humanos , Ratones , Ratones Noqueados , Esquizofrenia/metabolismoRESUMEN
BACKGROUND: Early life stress may have profound effects on brain health, yielding both short- and long-term cognitive or psychiatric impairment. Early life Social Instability Stress (SIS) in rodents has been used to model the effects of early chronic human stress. While many studies have assessed acute and short-term responses to this stressor, less attention has been paid to the lasting effects of early life stress in rodents. METHODS: The current study utilized SIS in young mice to assess the impact of early life adversity over the lifespan. Mice were assessed in adulthood between the ages of 18 to 66 weeks for changes in behaviors associated with anxiety, affect, sociability, aggression, motivation, and recognition memory. Additionally, mice were assessed for changes in glucocorticoid level and hippocampal mRNA expression in a subset of genes that display alterations in humans following exposure to stress (CRHR1, CRHR2, FKBP5, SLC6A4). RESULTS: Mice exposed to early SIS showed disrupted memory and increased hippocampal expression of FKBP5, CRHR2 and SLC6A4 mRNA compared to non-stressed mice. Importantly, there was a significant association between increased FKBP5 and CRHR2 with reduced recognition memory. Additionally, mice exposed to SIS showed increased responding on a progressive ratio schedule of reinforcement, indicating that reduction in memory performance was not mediated by decreased effort. CONCLUSIONS: Ecologically-relevant social stress in mice causes long-term decrements in recognition memory, possibly mediated by persistent changes in moderators of the stress cascade. Additionally, animals exposed to early life stress showed increased motivation for reward, which may contribute to a host of hedonic seeking behaviors throughout life. These data suggest that SIS can be used to evaluate therapeutic interventions to attenuate or reverse lasting effects of early life adversity.
Asunto(s)
Cognición , Hipocampo , Estrés Psicológico , Animales , Ratones , Expresión Génica , Hipocampo/metabolismo , ARN Mensajero/metabolismo , Estrés Psicológico/psicología , Trastornos de la MemoriaRESUMEN
Altered gamma-band electrophysiological activity in individuals with autism spectrum disorder (ASD) is well documented, and analogous gamma-band alterations are recapitulated in several preclinical murine models relevant to ASD. Such gamma-band activity is hypothesized to underlie local circuit processes. Gamma-band cross-frequency coupling (CFC), a related though distinct metric, interrogates local neural circuit signal integration. Several recent studies have observed perturbed gamma-band CFC in individuals with ASD, although the direction of change remains unresolved. It also remains unclear whether murine models relevant to ASD recapitulate this altered gamma-band CFC. As such, this study examined whether mice with parvalbumin (PV) cell-specific ablation of NMDA-R1 (PVcre/NR1fl/fl) demonstrated altered gamma-band CFC as compared with their control littermates (PVcre/NR1+/+-mice that do not have the PV cell-specific ablation of NMDA-R1). Ten mice of each genotype had 4 min of "resting" electroencephalography recorded and analyzed. First, resting electrophysiological power was parsed into the canonical frequency bands and genotype-related differences were subsequently explored so as to provide context for the subsequent CFC analyses. PVcre/NR1fl/fl mice exhibited an increase in resting power specific to the high gamma-band, but not other frequency bands, as compared with PVcre/NR1+/+. CFC analyses then examined both the standard magnitude (strength) of CFC and the novel metric PhaseMax-which denotes the phase of the lower frequency signal at which the peak higher frequency signal power occurred. PVcre/NR1fl/fl mice exhibited altered PhaseMax, but not strength, of gamma-band CFC as compared with PVcre/NR1+/+ mice. As such, this study suggests a potential novel metric to explore when studying neuropsychiatric disorders.
Asunto(s)
Ritmo Gamma/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/fisiología , Animales , Trastorno del Espectro Autista/fisiopatología , Modelos Animales de Enfermedad , Electroencefalografía/métodos , Fenómenos Electrofisiológicos/fisiología , Imagen por Resonancia Magnética/métodos , Masculino , Ratones , Ratones Endogámicos , Parvalbúminas/farmacología , Descanso/fisiologíaRESUMEN
Much evidence suggests that hypofunction of the N-methyl-d-aspartate glutamate receptor (NMDAR) may contribute broadly towards a subset of molecular, cognitive and behavioral abnormalities common among psychiatric and developmental diseases. However, little is known about the specific molecular changes that lead to NMDAR dysfunction. As such, personalized approaches to remediating NMDAR dysfunction based on a specific etiology remains a challenge. Sarcoma tyrosine kinase (Src) serves as a hub for multiple signaling mechanisms affecting GluN2 phosphorylation and can be disrupted by convergent alterations of various signaling pathways. We recently showed reduced Src signaling in post mortem tissue from schizophrenia patients, despite increased MK-801 binding and NMDA receptor complex expression in the postsynaptic density (PSD). These data suggest that Src dysregulation may be an important underlying mechanism responsible for reduced glutamate signaling. Despite this evidence for a central role of Src in NMDAR signaling, little is known about how reductions in Src activity might regulate phenotypic changes in cognition and behavior. As such, the current study sought to characterize behavioral and electrophysiological phenotypes in mice heterozygous for the Src Acl gene (Src+/- mice). Src+/- mice demonstrated decreased sociability and working memory relative to Src+/+ (WT) mice while no significant differences were seen on locomotive activity and anxiety-related behavior. In relation to WT mice, Src+/- mice showed decreased mid-latency P20 auditory event related potential (aERP) amplitudes, decreased mismatch negativity (MMN) and decreased evoked gamma power, which was only present in males. These data indicate that Src+/- mice are a promising new model to help understand the pathophysiology of these electrophysiological, behavioral and cognitive changes. As such, we propose that Src+/- mice can be used in the future to evaluate potential therapeutic approaches by targeting increased Src activity as a common final pathway for multiple etiologies of SCZ and other diseases characterized by reduced glutamate function.
Asunto(s)
Memoria a Corto Plazo , Conducta Social , Familia-src Quinasas/deficiencia , Animales , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Electroencefalografía , Electrofisiología , Potenciales Evocados/fisiología , Femenino , Masculino , Memoria a Corto Plazo/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Esquizofrenia/enzimología , Esquizofrenia/fisiopatología , Familia-src Quinasas/fisiologíaRESUMEN
Exposure to an intermittent, escalating dose of amphetamine induces a sensitized state that, both behaviourally and neurochemically, mirrors several features linked to the positive symptoms of schizophrenia. Increasingly it is being realized that cognitive deficits are a core component of schizophrenia; therefore we sought to assess the effects of inducing an amphetamine-sensitized state on memory (working and long-term) and cognitive flexibility, two cognitive domains impaired in schizophrenia. Rats were exposed to a sensitizing regimen of amphetamine (1-5 mg/kg; three times per week for 5 weeks; escalating at 1mg/kg per week) or saline. In experiment 1, animals were tested on an operant delayed non-match to position task (working memory). Experiment 2 used a standard fixed-platform location water maze task (long-term memory), while experiment 3 used a variable-platform location water maze task (long-term memory and working memory). Amphetamine-sensitized animals were not impaired on any of these tasks. In experiment 4, animals were assessed on a strategy selection task in which they were first required to learn to locate a food reward using a particular learning strategy (place or response) then to learn to shift to an alternate learning strategy (response or place). Amphetamine-sensitized animals were not impaired on this task. In the final experiment animals were found to be impaired in performance of the extra-dimensional shift component of an attentional set-shifting task. These results suggest that while amphetamine sensitization does not produce memory impairments similar to those seen in schizophrenia, it does produce strong impairments in set-shifting, suggesting changes in prefrontal function similar to those seen in schizophrenia.
Asunto(s)
Anfetamina/administración & dosificación , Atención/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/administración & dosificación , Memoria/efectos de los fármacos , Disposición en Psicología , Adaptación Psicológica/efectos de los fármacos , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/clasificación , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Schizophrenia is a mental disorder associated with profoundly disruptive positive and negative symptomology that result in difficulties building close relationships with others, performing daily tasks and sustaining independent living, resulting in poor social, vocational and occupational attainment (functional outcome). Mismatch Negativity (MMN) is a change in the sensory event-related potential that occurs in response to deviation from an established pattern of stimulation. Patients with schizophrenia show a reduction in MMN that is positively associated with impaired cognition and poor functional outcome. This has led to interest in MMN as a potential clinical and pre-clinical biomarker of fundamental neural processes responsible for reduced functional outcome. To date, relatively few studies have sought to assess MMN in non-human primates or rodents. The validity of these studies will be reviewed using criteria used to identify true deviance detection based MMN responses in human subjects. Although MMN has been difficult to establish in pre-clinical models the weight of evidence suggests that non-human animals show true deviance based MMN.
Asunto(s)
Variación Contingente Negativa/fisiología , Potenciales Evocados Auditivos/fisiología , Esquizofrenia/fisiopatología , Psicología del Esquizofrénico , Estimulación Acústica , Animales , Modelos Animales de Enfermedad , Electroencefalografía , HumanosRESUMEN
Gestational methylazoxymethanol acetate (MAM) exposure has been suggested to produce neural and behavioral abnormalities similar to those seen in schizophrenia. In order to assess MAM treatment as a model of schizophrenia, pregnant female rats were injected with MAM (22 mg/kg) on gestational day 17 and their offspring were assessed in adulthood on a series of cognitive tasks. The first experiment involved an attentional set-shifting task, a rodent analog of the Wisconsin card sort task. In experiment 2, animals were tested on the 5-choice serial reaction time task, a rodent analog of the continuous performance task. In the final experiment animals were assessed on a differential reinforcement of low rate of responding 20 s schedule of reinforcement (DRL-20), a task that is sensitive to changes in inhibitory control. In the first experiment, MAM-treated animals required a greater number of trials than controls to successfully learn an extradimensional shift on the set-shifting task, and had difficulties in learning to reverse a previously acquired discrimination. In contrast, MAM-treated animals showed little impairment on the 5-choice task, aside from a modest but consistent increase in premature responding. Finally, MAM exposed animals showed substantial impairments in DRL performance. Post-mortem analysis of brain tissue showed significant decreases in tissue weight in the hippocampus, parietal cortex, prefrontal cortex, and dorsal striatum of MAM-treated animals. These results support the notion that MAM treatment may simulate some aspects of schizophrenic cognition.
Asunto(s)
Encéfalo/efectos de los fármacos , Trastornos del Conocimiento/inducido químicamente , Acetato de Metilazoximetanol/análogos & derivados , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Esquizofrenia/etiología , Animales , Atrofia/inducido químicamente , Atrofia/patología , Atrofia/fisiopatología , Encéfalo/patología , Encéfalo/fisiopatología , Daño Encefálico Crónico/inducido químicamente , Daño Encefálico Crónico/patología , Daño Encefálico Crónico/fisiopatología , Trastornos del Conocimiento/fisiopatología , Trastornos del Conocimiento/psicología , Aprendizaje Discriminativo/efectos de los fármacos , Aprendizaje Discriminativo/fisiología , Modelos Animales de Enfermedad , Femenino , Discapacidades para el Aprendizaje/inducido químicamente , Discapacidades para el Aprendizaje/fisiopatología , Discapacidades para el Aprendizaje/psicología , Masculino , Acetato de Metilazoximetanol/toxicidad , Pruebas Neuropsicológicas , Embarazo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Efectos Tardíos de la Exposición Prenatal/psicología , Desempeño Psicomotor/efectos de los fármacos , Desempeño Psicomotor/fisiología , Ratas , Refuerzo en Psicología , Teratógenos/toxicidadRESUMEN
Fragile X is the most common monogenic disorder associated with intellectual disability (ID) and autism spectrum disorders (ASD). Additionally, many patients are afflicted with executive dysfunction, ADHD, seizure disorder and sleep disturbances. Fragile X is caused by loss of FMRP expression, which is encoded by the FMR1 gene. Both the fly and mouse models of fragile X are also based on having no functional protein expression of their respective FMR1 homologs. The fly model displays well defined cognitive impairments and structural brain defects and the mouse model, although having subtle behavioral defects, has robust electrophysiological phenotypes and provides a tool to do extensive biochemical analysis of select brain regions. Decreased cAMP signaling has been observed in samples from the fly and mouse models of fragile X as well as in samples derived from human patients. Indeed, we have previously demonstrated that strategies that increase cAMP signaling can rescue short term memory in the fly model and restore DHPG induced mGluR mediated long term depression (LTD) in the hippocampus to proper levels in the mouse model (McBride et al., 2005; Choi et al., 2011, 2015). Here, we demonstrate that the same three strategies used previously with the potential to be used clinically, lithium treatment, PDE-4 inhibitor treatment or mGluR antagonist treatment can rescue long term memory in the fly model and alter the cAMP signaling pathway in the hippocampus of the mouse model.
RESUMEN
Schizophrenia is associated with by severe disruptions in thought, cognition, emotion, and behavior. Patients show a marked increase in rates of smoking and nicotine dependence relative to nonaffected individuals, a finding commonly ascribed to the potential ameliorative effects of nicotine on symptom severity and cognitive impairment. Indeed, many studies have demonstrated improvement in patients following the administration of nicotine. Such findings have led to an increased emphasis on the development of therapeutic agents to target the nicotinic system as well as increasing the impetus to understand the genetic basis for nicotinic dysfunction in schizophrenia. The goal of this review article is to provide a critical summary of evidence for the role of the nicotinic system in schizophrenia. The first part will review the role of nicotine in normalization of primary dysfunctions and endophenotypical changes found in schizophrenia. The second part will provide a summary of genetic evidence linking polymorphisms in nicotinic receptor genes to smoking and schizophrenia. The third part will summarize attempts to treat schizophrenia using agents specifically targeting nicotinic and nicotinic receptor subtypes. Although currently available antipsychotic treatments are generally able to manage some aspects of schizophrenia (e.g., positive symptoms) they fail to address several other critically effected aspects of the disease. As such, the search for novel mechanisms to treat this disease is necessary.
Asunto(s)
Antipsicóticos/uso terapéutico , Nicotina/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Animales , Trastornos del Conocimiento/etiología , Electroencefalografía , Potenciales Evocados/efectos de los fármacos , Potenciales Evocados/genética , Humanos , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Esquizofrenia/genética , Esquizofrenia/fisiopatologíaRESUMEN
Standard dopamine therapies for schizophrenia are not efficacious for negative symptoms of the disease, including asociality. This reduced social behavior may be due to glutamatergic dysfunction within the amygdala, leading to increased fear and social anxiety. Several studies have demonstrated the prosocial effects of oxytocin in schizophrenia patients. Therefore, this study evaluates the effect of subchronic oxytocin on EEG activity in amygdala of mice during performance of the three-chamber social choice and open field tests following acute ketamine as a model of glutamatergic dysfunction. Oxytocin did not restore social deficits introduced by ketamine but did significantly increase sociality in comparison to the control group. Ketamine had no effect on time spent in the center during the open field trials, whereas oxytocin increased overall center time across all groups, suggesting a reduction in anxiety. Amygdala activity was consistent across all drug groups during social and nonsocial behavioral trials. However, oxytocin reduced overall amygdala EEG power during the two behavioral tasks. Alternatively, ketamine did not significantly affect EEG power throughout the tasks. Decreased EEG power in the amygdala, as caused by oxytocin, may be related to both reduced anxiety and increased social behaviors. Data suggest that separate prosocial and social anxiety pathways may mediate social preference.
Asunto(s)
Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/fisiología , Ansiedad , Oxitocina/administración & dosificación , Conducta Social , Animales , Ondas Encefálicas/efectos de los fármacos , Modelos Animales de Enfermedad , Electroencefalografía , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Ketamina/administración & dosificación , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Esquizofrenia/inducido químicamente , Esquizofrenia/fisiopatologíaRESUMEN
Studies suggest that abnormalities in glutamate and GABA signaling contribute to deficits in schizophrenia and related conditions and that these neurochemical abnormalities produce changes in electroencephalographic (EEG) indices, including event-related potentials and event-related power within specific frequency ranges. Furthermore, clinical studies suggest that a subset of EEG biomarkers is associated with symptoms. This review addresses the relationship between EEG and behavior in preclinical models of N-methyl-d-aspartate (NMDA)-receptor hypofunction, as well as how these models can be used to screen therapies. Data from schizophrenia patients are juxtaposed with data from animal models, and EEG and behavioral data from mice with disruption of NMDA receptors in excitatory and/or inhibitory neurons are then compared to the pattern observed in schizophrenia. Also discussed are results following exposure to potential therapeutic agents, including GABAB agonists. Furthermore, evidence demonstrates that elevated resting gamma power is associated with deficits in social interactions. Consistent with elevated baseline noise, excitatory neurons from transgenic mice show increased intrinsic excitability in in vitro-slice patch-clamp studies across model systems. GABAB receptor agonists reduce this excitability, improve gamma-band responses, and reverse behavioral deficits in mice. Data suggest that baseline gamma power is associated with social function and GABAB agonists may be useful for schizophrenia. Translational EEG biomarkers reflect target engagement and can contribute to the design of more efficient drug trials, likely accelerating the development of new therapeutics for central nervous system disorders.
Asunto(s)
Electroencefalografía , Potenciales Evocados , Receptores de GABA-B/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia , Animales , Conducta Animal , Biomarcadores , Modelos Animales de Enfermedad , Agonistas de Receptores GABA-B/uso terapéutico , Humanos , Ratones , Esquizofrenia/diagnóstico , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatología , Investigación Biomédica TraslacionalRESUMEN
BACKGROUND: Neuronal activity at gamma frequency is impaired in schizophrenia (SZ) and is considered critical for cognitive performance. Such impairments are thought to be due to reduced N-methyl-D-aspartate receptor (NMDAR)-mediated inhibition from parvalbumin interneurons, rather than a direct role of impaired NMDAR signaling on pyramidal neurons. However, recent studies suggest a direct role of pyramidal neurons in regulating gamma oscillations. In particular, a computational model has been proposed in which phasic currents from pyramidal cells could drive synchronized feedback inhibition from interneurons. As such, impairments in pyramidal neuron activity could lead to abnormal gamma oscillations. However, this computational model has not been tested experimentally and the molecular mechanisms underlying pyramidal neuron dysfunction in SZ remain unclear. METHODS: In the present study, we tested the hypothesis that SZ-related phenotypes could arise from reduced NMDAR signaling in pyramidal neurons using forebrain pyramidal neuron specific NMDA receptor 1 knockout mice. RESULTS: The mice displayed increased baseline gamma power, as well as sociocognitive impairments. These phenotypes were associated with increased pyramidal cell excitability due to changes in inherent membrane properties. Interestingly, mutant mice showed decreased expression of GIRK2 channels, which has been linked to increased neuronal excitability. CONCLUSIONS: Our data demonstrate for the first time that NMDAR hypofunction in pyramidal cells is sufficient to cause electrophysiological, molecular, neuropathological, and behavioral changes related to SZ.
Asunto(s)
Encéfalo/fisiología , Proteínas del Tejido Nervioso/metabolismo , Células Piramidales/fisiología , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Ritmo beta/fisiología , Colecistoquinina/metabolismo , Potenciales Evocados Auditivos , Canales de Potasio Rectificados Internamente Asociados a la Proteína G/metabolismo , Ritmo Gamma/fisiología , Glutamato Descarboxilasa/metabolismo , Memoria a Corto Plazo/fisiología , Ratones Noqueados , Proteínas del Tejido Nervioso/genética , Comportamiento de Nidificación/fisiología , Vías Nerviosas/fisiología , Parvalbúminas/metabolismo , Prosencéfalo/fisiología , Receptores AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Conducta Social , Somatostatina/metabolismo , Memoria Espacial/fisiología , Ritmo Teta/fisiologíaRESUMEN
Addiction is considered to be a brain disease caused by chronic exposure to drugs. Sensitization of brain dopamine (DA) systems partly mediates this effect. Pathological gambling (PG) is considered to be a behavioral addiction. Therefore, PG may be caused by chronic exposure to gambling. Identifying a gambling-induced sensitization of DA systems would support this possibility. Gambling rewards evoke DA release. One episode of slot machine play shifts the DA response from reward delivery to onset of cues (spinning reels) for reward, in line with temporal difference learning principles. Thus, conditioned stimuli (CS) play a key role in DA responses to gambling. In primates, DA response to a CS is strongest when reward probability is 50%. Under this schedule the CS elicits an expectancy of reward but provides no information about whether it will occur on a given trial. During gambling, a 50% schedule should elicit maximal DA release. This closely matches reward frequency (46%) on a commercial slot machine. DA release can contribute to sensitization, especially for amphetamine. Chronic exposure to a CS that predicts reward 50% of the time could mimic this effect. We tested this hypothesis in three studies with rats. Animals received 15 × 45-min exposures to a CS that predicted reward with a probability of 0, 25, 50, 75, or 100%. The CS was a light; the reward was a 10% sucrose solution. After training, rats received a sensitizing regimen of five separate doses (1 mg/kg) of d-amphetamine. Lastly they received a 0.5 or 1 mg/kg amphetamine challenge prior to a 90-min locomotor activity test. In all three studies the 50% group displayed greater activity than the other groups in response to both challenge doses. Effect sizes were modest but consistent, as reflected by a significant group × rank association (Ï = 0.986, p = 0.025). Chronic exposure to a gambling-like schedule of reward predictive stimuli can promote sensitization to amphetamine much like exposure to amphetamine itself.