RESUMEN
Early motor and sensory developmental delays precede Autism Spectrum Disorder (ASD) diagnosis and may serve as early indicators of ASD. The literature on sensorimotor development in animal models is sparse, male centered, and has mixed findings. We characterized early development in a prenatal valproic acid (VPA) model of ASD and found sex-specific developmental delays in VPA rats. We created a developmental composite score combining 15 test readouts, yielding a reliable gestalt measure spanning physical, sensory, and motor development, that effectively discriminated between VPA and control groups. Considering the heterogeneity in ASD phenotype, the developmental composite offers a robust metric that can enable comparison across different animal models of ASD and can serve as an outcome measure for early intervention studies.
Asunto(s)
Trastorno del Espectro Autista , Efectos Tardíos de la Exposición Prenatal , Embarazo , Ratas , Masculino , Femenino , Humanos , Animales , Ácido Valproico/efectos adversos , Trastorno del Espectro Autista/inducido químicamente , Trastorno del Espectro Autista/diagnóstico , Conducta Animal , Modelos Animales de EnfermedadRESUMEN
Repeated exposure to adverse experiences in early life, termed Early Life Stress (ELS), can increase anxiety disorders later in life. Anxiety is directly associated with curiosity, a form of intrinsic drive state associated with increased novelty-seeking behaviour and risk taking for challenging opportunities and could probably modulate learning and memory. In humans, elevated curiosity during adolescence tends to elicit increased exploration, novelty seeking, high risk-taking behaviour and heightened emotionality. Such behaviours are beneficial in maintaining social skills and cognitive functions later in life. We investigated whether ELS-induced anxiety impacts curiosity-like behaviour at adolescence in an animal model. ELS was induced by subjecting Sprague Dawley rat pups to maternal separation and isolation (MS) stress during the stress hyporesponsive period (SHRP) from post-natal days (PND) 4-PND 14. This rat model was tested for anxiety, spontaneous exploratory behaviour and curiosity-like behaviour in a custom-designed arena during adolescence (PND 30-45). ELS-induced changes in the stress were confirmed by corticosterone, while, basal dopamine level was estimated to understand the neurochemical basis of MS stress-induced changes in curiosity. We observed an increase in the levels of anxiety and intrinsic drive state such as curiosity-like behaviour, which was associated with elevated plasma corticosterone and dopamine in MS animals during adolescence suggesting the impact of ELS during SHRP on adolescent behaviour.
Asunto(s)
Experiencias Adversas de la Infancia , Conducta Exploratoria , Animales , Ansiedad/etiología , Ansiedad/psicología , Trastornos de Ansiedad , Corticosterona , Dopamina , Humanos , Privación Materna , Ratas , Ratas Sprague-Dawley , Estrés Psicológico/psicologíaRESUMEN
Early life stress is known to influence affective and cognitive functions in later life but comprehensive explanation for the impact of early life stress on attentional functions, behavioural control and social behaviour is inadequate. The early life stress was induced by exposing rat pups to 6 h of maternal separation and isolation (MS) stress from postnatal days 4-14 i.e. during SHRP period. The long-term impact of MS in these rats was evaluated by assessing anxiety, sociability, social preference, spatial learning and memory along with a detailed evaluation of attentional functions during young adulthood period. Adult male MS rats showed increased anxiety-like behaviour, impaired flexibility in social interactions, and increased reward-seeking behaviour. MS rats also showed faster spatial learning in the partially baited radial arm maze and exhibited moderately enhanced sustained attention in the 5-choice serial reaction time task (5CSRTT). These results suggest that early MS has both positive and negative consequences in adulthood. Increased cognitive ability in MS rats, as evidenced by the improved sustained attention and spatial learning and memory, is usually advantageous and indicates positive influences of early stressors that might lead to the development of resilience and enhanced compensatory mechanisms later in adulthood. MS stress has compromised flexibility in social behaviour that promotes solitary lifestyle and social isolation. Heightened reward-seeking behaviour, as shown by the MS rats, could be a predisposing factor for substance abuse and addiction. Thus, our study highlights the crucial and differential impact of early life challenges on behaviour during adulthood and suggests that the positive aspects could be an asset that may be utilized to suppress the negative effects of early life stress in adulthood.
Asunto(s)
Atención/fisiología , Relaciones Interpersonales , Privación Materna , Aprendizaje Espacial/fisiología , Estrés Psicológico/psicología , Animales , Animales Recién Nacidos , Ansiedad/psicología , Femenino , Masculino , Embarazo , Ratas , Ratas Wistar , Conducta Social , Factores de TiempoRESUMEN
Attention is foundational to efficient perception and optimal goal driven behavior. Intact attentional processing is crucial for the development of social and communication skills. Deficits in attention are therefore likely contributors to the core pathophysiology of autism spectrum disorder (ASD). Clinical evidence in ASD is suggestive of impairments in attention and its control, but the underlying mechanisms remain elusive. We examined sustained, spatially divided attention in a prenatal valproic acid (VPA) model of ASD using the 5-choice serial reaction time task (5-CSRTT). As compared to controls, male and female VPA rats had progressively lower accuracy and higher omissions with increasing attentional demands during 5-CSRTT training, and showed further performance decrements when subjected to parametric task manipulations. It is noteworthy that although VPA exposure induced attentional deficits in both sexes, there were task parameter specific sex differences. Importantly, we did not find evidence of impulsivity or motivational deficits in VPA rats but we did find reduced social preference, as well as sensorimotor deficits that suggest pre-attentional information processing impairments. Importantly, with fixed rules, graded difficulty levels, and more time, VPA rats could be successfully trained on the attentional task. To the best of our knowledge, this is the first study examining attentional functions in a VPA model. Our work underscores the need for studying both sexes in ASD animal models and validates the use of the VPA model in the quest for mechanistic understanding of aberrant attentional functions and for evaluating suitable therapeutic targets. Autism Res 2017, 10: 1929-1944. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We studied rats prenatally exposed to valproic acid (VPA), an established rodent model of autism. Both male and female VPA rats had a range of attentional impairments with sex-specific characteristics. Importantly, with fixed rules, graded difficulty levels, and more time, VPA rats could be successfully trained on the attentional task. Our work validates the use of the VPA model in the quest for evaluating suitable therapeutic targets for improving attentional performance.
Asunto(s)
Atención/fisiología , Trastorno del Espectro Autista/fisiopatología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Ácido Valproico/administración & dosificación , Animales , Modelos Animales de Enfermedad , Femenino , Masculino , Embarazo , Ratas , Ratas Sprague-Dawley , Tiempo de ReacciónRESUMEN
Subiculum is an important structure of hippocampal formation and is a part of intra hippocampal network involved in spatial information processing. However, relatively very few studies are available in literature demonstrating the explicit role of subiculum in spatial information processing. The present study investigated the cholinergic modulation of subicular theta-gamma activity on spatial learning and memory functions in rats. The cholinergic projections to ventral subiculum were selectively eliminated using 192 IgG-SAPORIN. Eliminations of cholinergic inputs to ventral subiculum significantly reduced the subicular theta and enhanced the gamma activity during active wake and REM sleep states. In addition, the spatial learning was severely impaired following cholinergic elimination of ventral subiculum. The ChAT immunocytochemical studies showed sparse distribution of cholinergic fibers in the ventral subiculum confirming the cholinergic elimination to ventral subiculum. Cholinotoxic infusions to ventral subiculum did not alter the hippocampal cholinergic innervations and retained the hippocampal theta and gamma activities. The present findings support that cholinergic modulation of subicular theta-gamma oscillations is crucial for spatial information processing.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Ritmo Gamma/efectos de los fármacos , Hipocampo/efectos de los fármacos , Inmunotoxinas/farmacología , Proteínas Inactivadoras de Ribosomas Tipo 1/farmacología , Aprendizaje Espacial/efectos de los fármacos , Ritmo Teta/efectos de los fármacos , Animales , Colina O-Acetiltransferasa/metabolismo , Fibras Colinérgicas/efectos de los fármacos , Fibras Colinérgicas/metabolismo , Hipocampo/metabolismo , Masculino , Ratas , Ratas Wistar , SaporinasRESUMEN
The cellular and molecular effects of stress on the amygdala are strikingly different compared with those in the hippocampus. Previous findings on stress-induced plasticity were based primarily on postmortem analysis within individual areas. However, little is known about how stress affects dynamic changes and interactions in neuronal activity between the two areas. Hence, we simultaneously monitored in vivo activity of neuronal populations located in hippocampal areas CA1 and CA3 and the lateral amygdala (LA) in rats during and after chronic immobilization stress. The amplitude of auditory-evoked potentials (AEPs) in the hippocampus increased transiently only after a single 2 h stress but not when it was repeated for 10 d. In contrast, both acute and chronic stress caused a persistent increase in AEPs in the LA. Chronic stress also elicited a sustained increase in the LA but a decrease in the hippocampus in the evoked power of gamma and beta frequencies. Moreover, beta and gamma synchrony was reduced between areas CA1 and CA3 but enhanced between the LA and hippocampus after chronic stress. Granger causality spectra revealed a strong directional influence from the LA to area CA1 that persisted throughout and even 10 d after chronic stress. However, directional coupling from hippocampal area CA3 to CA1 became weaker at the end of chronic stress. Thus, our findings suggest that the growing dominance of amygdalar activity over the hippocampus during and even after chronic stress may contribute to the enhanced emotional symptoms, alongside impaired cognitive function, seen in stress-related psychiatric disorders.
Asunto(s)
Amígdala del Cerebelo/fisiología , Hipocampo/fisiología , Red Nerviosa/fisiología , Estrés Psicológico/fisiopatología , Animales , Masculino , Vías Nerviosas/fisiología , Ratas , Ratas Wistar , Restricción Física/efectos adversos , Estrés Psicológico/psicologíaRESUMEN
Mice are favourite subjects in molecular and genetic memory research and frequently studied with classical fear conditioning paradigms that use an auditory cue (conditioned stimulus, CS(+)) to predict an aversive, unconditioned stimulus (US). Yet the conditions that control fear memory specificity and generalisation and their behavioural expression in such conditioned mice have not been analysed systematically. In the current study we addressed these issues in the most widely used mouse strain of behavioural genetics, C57Bl/6. In keeping with findings in other species we demonstrate the dependence of fear memory generalisation on training intensity (i.e. both US intensity and the number of CS(+) and US applied) after both excitatory (explicitly paired presentation of CS(+) and US) and inhibitory training (explicitly unpaired presentation of CS(+) and US). Furthermore, inhibitory overtraining was associated with changes of uncued anxiety-like behaviour in a light/dark exploration test, indicative of an emotional sensitisation reaction as consequence of a lack of US predictability. Together our results describe the qualitatively and quantitatively different increases of defensive behaviour in response to conditioned stimuli of different salience and identify training conditions that lead to fear memory generalisation and emotional sensitisation in C57Bl/6 inbred mice.
Asunto(s)
Conducta Animal/fisiología , Condicionamiento Clásico/fisiología , Miedo/fisiología , Generalización Psicológica/fisiología , Estimulación Acústica , Animales , Ansiedad , Señales (Psicología) , Electrochoque , Conducta Exploratoria , Extinción Psicológica , Masculino , Memoria/fisiología , Ratones , Ratones Endogámicos C57BL , Actividad Motora , Reflejo de Sobresalto , Factores de TiempoRESUMEN
The amygdalohippocampal circuit plays a pivotal role in Pavlovian fear memory. We simultaneously recorded electrical activity in the lateral amygdala (LA) and the CA1 area of the hippocampus in freely behaving fear-conditioned mice. Patterns of activity were related to fear behavior evoked by conditioned and indifferent sensory stimuli and contexts. Rhythmically synchronized activity at theta frequencies increased between the LA and the CA1 after fear conditioning and became significant during confrontation with conditioned fear stimuli and expression of freezing behavior. Synchronization of theta activities in the amygdalohippocampal network represents a neuronal correlate of conditioned fear, apt to improve neuronal communication during memory retrieval.