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Genes Feb 2023The startle response can be defined as a reflexive reaction to the sudden appearance of a novel stimulus that influences the survival and resilience of animals. In...
The startle response can be defined as a reflexive reaction to the sudden appearance of a novel stimulus that influences the survival and resilience of animals. In domesticated species, the behavioral component of the startle response can, in some cases, cause serious injury to the animal or human handlers if inappropriately expressed. Here, we describe a longitudinal study in a population of stock-type horses that quantified behavioral startle responses elicited by the presentation of a sudden novel object (rapidly opening umbrella). The study was performed in weanling foals across four consecutive years ( = 74, mean age = 256 days). Behavioral assays for the startle response phenotype focused on six behavioral variables: latency to return to the feed pan (seconds), maximum distance fled (meters), proportion of time spent walking or trotting (seconds), and how long a horse spent standing facing away from or toward the novel object. We observed behavioral startle response variables in relation to cardiac response, age, and sex for each individual. Each horse's cardiac startle response pattern was determined and categorized into heart rate response cluster groups identified as accelerators and decelerators. Using principal component analysis (PCA) with a factor rotation, we identified "startle response" phenotypes that summarize the behavioral and physiological variables. The largest component of variation, Factor 1, comprised 32.5% of the behavioral variable with a positive correlation with latency and distance, and was not influenced by sex or age. Factor 2 comprised 23.2% of the variation, and was positively correlated with activity level performed such as proportion of time spent walking and/or trotting. Horses with the accelerator type cardiac response had significantly higher Factor 1 scores than decelerators but did not differ in Factor 2. Future work includes expanding our sample size to conduct a genome-wide association study (GWAS) to identify novel genetic loci influencing behavioral startle reactions using recorded behavioral and physiological phenotypes.
Topics: Humans; Animals; Horses; Genome-Wide Association Study; Longitudinal Studies; Reflex, Startle; Phenotype; Genetic Loci
PubMed: 36980865
DOI: 10.3390/genes14030593 -
Neuroscience and Biobehavioral Reviews May 2023The startle response consists of whole-body muscle contractions, eye-blink, accelerated heart rate, and freezing in response to a strong, sudden stimulus. It is... (Review)
Review
The startle response consists of whole-body muscle contractions, eye-blink, accelerated heart rate, and freezing in response to a strong, sudden stimulus. It is evolutionarily preserved and can be observed in any animal that can perceive sensory signals, indicating the important protective function of startle. Startle response measurements and its alterations have become a valuable tool for exploring sensorimotor processes and sensory gating, especially in the context of pathologies of psychiatric disorders. The last reviews on the neural substrates underlying acoustic startle were published around 20 years ago. Advancements in methods and techniques have since allowed new insights into acoustic startle mechanisms. This review is focused on the neural circuitry that drives the primary acoustic startle response in mammals. However, there have also been very successful efforts to identify the acoustic startle pathway in other vertebrates and invertebrates in the past decades, so at the end we briefly summarize these studies and comment on the similarities and differences between species.
Topics: Animals; Reflex, Startle; Acoustic Stimulation; Mammals
PubMed: 36914078
DOI: 10.1016/j.neubiorev.2023.105129 -
Psychopharmacology Apr 2023The dopamine D4 receptors (DRD4) play a key role in numerous brain functions and are involved in the pathogenesis of various psychiatric disorders. DRD4 ligands have...
RATIONALE
The dopamine D4 receptors (DRD4) play a key role in numerous brain functions and are involved in the pathogenesis of various psychiatric disorders. DRD4 ligands have been shown to moderate anxiety, reward and depression-like behaviours, and cognitive impairments. Despite a series of promising but ambiguous findings, the therapeutic advantages of DRD4 stimulation remain elusive.
OBJECTIVES
The investigation focused on the behavioural effects of the recently developed DRD4 agonist, APH199, to evaluate its impact on anxiety, anhedonia, behavioural despair, establishment and retrieval of alcohol reinforcement, and amphetamine (AMPH)-induced symptoms.
METHODS
Male C57BL/6 J mice and Sprague-Dawley rats were examined in five independent experiments. We assessed APH199 (0.1-5 mg/kg, i.p.) effects on a broad range of behavioural parameters in the open field (OF) test, conditioned place preference test (CPP), elevated plus maze (EPM), light-dark box (LDB), novelty suppressed feeding (NSF), forced swim test (FST), sucrose preference test (SPT), AMPH-induced hyperlocomotion test (AIH), and prepulse inhibition (PPI) of the acoustic startle response in AMPH-sensitized rats.
RESULTS
APH199 caused mild and sporadic anxiolytic and antidepressant effects in EPM and FST, but no remarkable impact on behaviour in other tests in mice. However, we found a significant increase in AMPH-induced hyperactivity, suggesting an exaggeration of the psychotic-like responses in the AMPH-sensitized rats.
CONCLUSIONS
Our data challenged the hypothesis of the therapeutic benefits of DRD4 agonists, pointing out a possible aggravation of psychosis. We suggest a need for further preclinical studies to ensure the safety of antipsychotics with DRD4 stimulating properties.
Topics: Mice; Rats; Male; Animals; Receptors, Dopamine D4; Dopamine Agonists; Reflex, Startle; Rats, Sprague-Dawley; Mice, Inbred C57BL; Amphetamine; Models, Animal; Behavior, Animal
PubMed: 36854793
DOI: 10.1007/s00213-023-06347-1 -
Current Neuropharmacology 2023Schizophrenia is a chronic and severe mental disorder with high heterogeneity in its symptoms clusters. The effectiveness of drug treatments for the disorder is far from...
Schizophrenia is a chronic and severe mental disorder with high heterogeneity in its symptoms clusters. The effectiveness of drug treatments for the disorder is far from satisfactory. It is widely accepted that research with valid animal models is essential if we aim at understanding its genetic/ neurobiological mechanisms and finding more effective treatments. The present article presents an overview of six genetically-based (selectively-bred) rat models/strains, which exhibit neurobehavioral schizophrenia-relevant features, i.e., the Apomorphine-susceptible (APO-SUS) rats, the Low-prepulse inhibition rats, the Brattleboro (BRAT) rats, the Spontaneously Hypertensive rats (SHR), the Wisket rats and the Roman High-Avoidance (RHA) rats. Strikingly, all the strains display impairments in prepulse inhibition of the startle response (PPI), which remarkably, in most cases are associated with novelty-induced hyperlocomotion, deficits of social behavior, impairment of latent inhibition and cognitive flexibility, or signs of impaired prefrontal cortex (PFC) function. However, only three of the strains share PPI deficits and dopaminergic (DAergic) psychostimulant-induced hyperlocomotion (together with prefrontal cortex dysfunction in two models, the APO-SUS and RHA), which points out that alterations of the mesolimbic DAergic circuit are a schizophrenia-linked trait that not all models reproduce, but it characterizes some strains that can be valid models of schizophrenia-relevant features and drug-addiction vulnerability (and thus, dual diagnosis). We conclude by putting the research based on these genetically-selected rat models in the context of the Research Domain Criteria (RDoC) framework, suggesting that RDoC-oriented research programs using selectively-bred strains might help to accelerate progress in the various aspects of the schizophrenia-related research agenda.
Topics: Rats; Animals; Schizophrenia; Rats, Brattleboro; Prepulse Inhibition; Reflex, Startle; Apomorphine; Dopamine; Disease Models, Animal
PubMed: 36809938
DOI: 10.2174/1570159X21666230221093644 -
Neuroreport Mar 2023The potassium voltage-gated channel subfamily Q member 4 (KCNQ4) subunit forms channels responsible for M-current, a muscarine-sensitive potassium current regulating...
The potassium voltage-gated channel subfamily Q member 4 (KCNQ4) subunit forms channels responsible for M-current, a muscarine-sensitive potassium current regulating neuronal excitability. In contrast to other KCNQ subunits, its expression is restricted to the cochlear outer hair cells, the auditory brainstem and other brainstem nuclei in a great overlap with structures involved in startle reflex. We aimed to show whether startle reflexis affected by the loss of KCNQ4 subunit and whether these alterations are similar to the ones caused by brainstem hyperexcitability. Young adult KCNQ4 knockout mice and wild-type littermates, as well as mice expressing hM3D chemogenetic actuator in the pontine caudal nucleus and neurons innervating it were used for testing acoustic startle. The acoustic startle reflex was significantly increased in knockout mice compared with wild-type littermates. When mice expressing human M3 muscarinic (hM3D) in nuclei related to startle reflex were tested, a similar increase of the first acoustic startle amplitude and a strong habituation of the further responses was demonstrated. We found that the acoustic startle reflex is exaggerated and minimal habituation occurs in KCNQ4 knockout animals. These changes are distinct from the effects of the hyperexcitability of nuclei involved in startle. One can conclude that the exaggerated startle reflex found with the KCNQ4 subunit deletion is the consequence of both the cochlear damage and the changes in neuronal excitability of startle networks.
Topics: Animals; Mice; Brain Stem; KCNQ Potassium Channels; Mice, Knockout; Neurons; Reflex, Startle
PubMed: 36789839
DOI: 10.1097/WNR.0000000000001883 -
Cells Jan 2023Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder caused by a chromosomic microdeletion (7q11.23). WBS has been modeled by a mouse line having a complete...
Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder caused by a chromosomic microdeletion (7q11.23). WBS has been modeled by a mouse line having a complete deletion (CD) of the equivalent mouse locus. This model has been largely used to investigate the etiopathological mechanisms of WBS, although pharmacological therapies have not been identified yet. Surprisingly, CD mice were so far mainly tested in adulthood, despite the developmental nature of WBS and the critical relevance of early timing for potential treatments. Here we provide for the first time a phenotypic characterization of CD mice of both sexes during infancy and adolescence, i.e., between birth and 7 weeks of age. CD pups of both sexes showed reduced body growth, delayed sensory development, and altered patterns of ultrasonic vocalizations and exploratory behaviors. Adolescent CD mice showed reduced locomotion and acoustic startle response, and altered social interaction and communication, the latter being more pronounced in female mice. Juvenile CD mutants of both sexes also displayed reduced brain weight, cortical and hippocampal dendritic length, and spine density. Our findings highlight the critical relevance of early neurobehavioral alterations as biomarkers of WBS pathology, underlying the importance of adolescence for identifying novel therapeutic targets for this neurological disorder.
Topics: Male; Mice; Female; Animals; Williams Syndrome; Reflex, Startle; Disease Models, Animal; Hippocampus
PubMed: 36766733
DOI: 10.3390/cells12030391 -
Brain, Behavior, and Immunity Mar 2023Prenatal infections can increase the risk of developing psychiatric disorders such as schizophrenia in the offspring, especially when combined with other postnatal...
Prenatal infections can increase the risk of developing psychiatric disorders such as schizophrenia in the offspring, especially when combined with other postnatal insults. Here, we tested, in a rat model of prenatal immune challenge by the viral mimic polyriboinosinic-polyribocytidilic acid, whether maternal immune activation (MIA) affects the endocannabinoid system and endocannabinoid-mediated modulation of dopamine functions. Experiments were performed during adolescence to assess i) the behavioral endophenotype (locomotor activity, plus maze, prepulse inhibition of startle reflex); ii) the locomotor activity in response to Δ9-Tetrahydrocannabinol (THC) and iii) the properties of ventral tegmental area (VTA) dopamine neurons in vivo and their response to THC; iv) endocannabinoid-mediated synaptic plasticity in VTA dopamine neurons; v) the expression of cannabinoid receptors and enzymes involved in endocannabinoid synthesis and catabolism in mesolimbic structures and vi) MIA-induced neuroinflammatory scenario evaluated by measurements of levels of cytokine and neuroinflammation markers. We revealed that MIA offspring displayed an altered locomotor activity in response to THC, a higher bursting activity of VTA dopamine neurons and a lack of response to cumulative doses of THC. Consistently, MIA adolescence offspring showed an enhanced 2-arachidonoylglycerol-mediated synaptic plasticity and decreased monoacylglycerol lipase activity in mesolimbic structures. Moreover, they displayed a higher expression of cyclooxygenase 2 (COX-2) and ionized calcium-binding adaptor molecule 1 (IBA-1), associated with latent inflammation and persistent microglia activity. In conclusion, we unveiled neurobiological mechanisms whereby inflammation caused by MIA influences the proper development of endocannabinoid signaling that negatively impacts the dopamine system, eventually leading to psychotic-like symptoms in adulthood.
Topics: Pregnancy; Female; Rats; Male; Animals; Humans; Endocannabinoids; Dopamine; Signal Transduction; Schizophrenia; Dopaminergic Neurons; Prenatal Exposure Delayed Effects
PubMed: 36746342
DOI: 10.1016/j.bbi.2023.02.002 -
Morphological and sensorimotor phenotypes in a zebrafish CHARGE syndrome model are domain-dependent.Genes, Brain, and Behavior Jun 2023CHARGE syndrome is a heterogeneous disorder characterized by a spectrum of defects affecting multiple tissues and behavioral difficulties such as autism,...
CHARGE syndrome is a heterogeneous disorder characterized by a spectrum of defects affecting multiple tissues and behavioral difficulties such as autism, attention-deficit/hyperactivity disorder, obsessive-compulsive disorder, anxiety, and sensory deficits. Most CHARGE cases arise from de novo, loss-of-function mutations in chromodomain-helicase-DNA-binding-protein-7 (CHD7). CHD7 is required for processes such as neuronal differentiation and neural crest cell migration, but how CHD7 affects neural circuit function to regulate behavior is unclear. To investigate the pathophysiology of behavioral symptoms in CHARGE, we established a mutant chd7 zebrafish line that recapitulates multiple CHARGE phenotypes including ear, cardiac, and craniofacial defects. Using a panel of behavioral assays, we found that chd7 mutants have specific auditory and visual behavior deficits that are independent of defects in sensory structures. Mauthner cell-dependent short-latency acoustic startle responses are normal in chd7 mutants, while Mauthner-independent long-latency responses are reduced. Responses to sudden decreases in light are also reduced in mutants, while responses to sudden increases in light are normal, suggesting that the retinal OFF pathway may be affected. Furthermore, by analyzing multiple chd7 alleles we observed that the penetrance of morphological and behavioral phenotypes is influenced by genetic background but that it also depends on the mutation location, with a chromodomain mutation causing the highest penetrance. This pattern is consistent with analysis of a CHARGE patient dataset in which symptom penetrance was highest in subjects with mutations in the CHD7 chromodomains. These results provide new insight into the heterogeneity of CHARGE and will inform future work to define CHD7-dependent neurobehavioral mechanisms.
Topics: Animals; CHARGE Syndrome; Zebrafish; DNA-Binding Proteins; Reflex, Startle; Phenotype; Mutation
PubMed: 36717082
DOI: 10.1111/gbb.12839 -
Neuroscience Mar 2023The contactin-associated protein-like 2 (CNTNAP2) gene encodes for the CASPR2 protein, which plays an essential role in neurodevelopment. Mutations in CNTNAP2 are...
Differences in Startle and Prepulse Inhibition in Contactin-associated Protein-like 2 Knock-out Rats are Associated with Sex-specific Alterations in Brainstem Neural Activity.
The contactin-associated protein-like 2 (CNTNAP2) gene encodes for the CASPR2 protein, which plays an essential role in neurodevelopment. Mutations in CNTNAP2 are associated with neurodevelopmental disorders, including autism spectrum disorder and schizophrenia. Rats with a loss of function mutation in the Cntnap2 gene show increased acoustic startle response (ASR) and decreased prepulse inhibition (PPI). The neural basis of this altered auditory processing in Cntnap2 knock-out rats is currently unknown. Auditory brainstem recordings previously revealed no differences between the genotypes. The next step is to investigate brainstem structures outside of the primary auditory pathway that mediate ASR and PPI, which are the pontine reticular nucleus (PnC) and pedunculopontine tegmentum (PPTg), respectively. Multi-unit responses from the PnC and PPTg in vivo of the same rats revealed sex-specific effects of loss of CASPR2 expression on PnC activity, but no effects on PPTg activity. Female Cntnap2 rats showed considerably increased PnC firing rates compared with female wildtypes, whereas the difference between the genotypes was modest in male rats. In contrast, for both females and males we found meager differences between the genotypes for PPTg firing rates and inhibition of PnC firing rates, indicating that altered firing rates of these brainstem structures are not responsible for decreased PPI in Cntnap2 rats. We conclude that the auditory processing changes seen in Cntnap2 rats are associated with, but cannot be fully explained by, differences in PnC firing rates, and that a loss of function mutation in the Cntnap2 gene has differential effects depending on sex.
Topics: Rats; Male; Female; Animals; Prepulse Inhibition; Reflex, Startle; Autism Spectrum Disorder; Acoustic Stimulation; Brain Stem; Contactins; Neural Inhibition
PubMed: 36708798
DOI: 10.1016/j.neuroscience.2023.01.020 -
NPJ Breast Cancer Jan 2023Multigenic tests represent an essential tool for the selection of adjuvant therapy in estrogen-positive/HER2-negative (ER + /HER2-) early breast cancer (BC). The...
Multigenic tests represent an essential tool for the selection of adjuvant therapy in estrogen-positive/HER2-negative (ER + /HER2-) early breast cancer (BC). The workflow of these tests, either if they are externalized or carried out in-house, generates a workload for the pathology laboratories, that is often underestimated and may affect timely therapy initiation. Here, we describe the evolving role of pathology laboratories in using multigenic tests and, more in general, in providing adequate tissue for molecular analyses. Moreover, we propose a “reflex testing” model, in which pathologists, based on pre-specified and shared criteria, are expected to action multigene testing independently of multidisciplinary team discussion in ER + /HER2- BC patients, in order to optimize turnaround time and proper therapy intervention.
PubMed: 36697419
DOI: 10.1038/s41523-023-00506-5