scholarly journals Lost in translation: no effect of repeated optogenetic cortico-striatal stimulation on compulsivity in rats

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Amanda R. de Oliveira ◽  
Adriano E. Reimer ◽  
Gregory J. Simandl ◽  
Sumedh S. Nagrale ◽  
Alik S. Widge
Keyword(s):  
Optical Fibers ◽  
Evoked Potential ◽  
Inbred Mice ◽  
Compulsive Behavior ◽  
Set Shifting ◽  
Stimulation Protocol ◽  
Attentional Set Shifting ◽  
Marble Burying ◽  
Lost In Translation ◽  
Synaptic Weighting

AbstractThe orbitofrontal cortex–ventromedial striatum (OFC–VMS) circuitry is widely believed to drive compulsive behavior. Hyperactivating this pathway in inbred mice produces excessive and persistent self-grooming, which has been considered a model for human compulsivity. We aimed to replicate these findings in outbred rats, where there are few reliable compulsivity models. Male Long-Evans rats implanted with optical fibers into VMS and with opsins delivered into OFC received optical stimulation at parameters that produce OFC–VMS plasticity and compulsive grooming in mice. We then evaluated rats for compulsive self-grooming at six timepoints: before, during, immediately after, and 1 h after each stimulation, 1 and 2 weeks after the ending of a 6-day stimulation protocol. To further test for effects of OFC–VMS hyperstimulation, we ran animals in three standard compulsivity assays: marble burying, nestlet shredding, and operant attentional set-shifting. OFC–VMS stimulation did not increase self-grooming or induce significant changes in nestlet shredding, marble burying, or set-shifting in rats. Follow-on evoked potential studies verified that the stimulation protocol altered OFC–VMS synaptic weighting. In sum, although we induced physiological changes in the OFC–VMS circuitry, we could not reproduce in a strongly powered study in rats a model of compulsive behavior previously reported in mice. This suggests possible limitations to translation of mouse findings to species higher on the phylogenetic chain.

scholarly journals Lost in translation: No effect of repeated optogenetic cortico-striatal stimulation on compulsivity in rats

2020 ◽  
Author(s):  
Amanda R. de Oliveira ◽  
Adriano E. Reimer ◽  
Gregory J. Simandl ◽  
Sumedh S. Nagrale ◽  
Alik S. Widge
Keyword(s):  
Optical Fibers ◽  
Evoked Potential ◽  
Inbred Mice ◽  
Physiological Changes ◽  
Compulsive Behavior ◽  
Set Shifting ◽  
Stimulation Protocol ◽  
Marble Burying ◽  
Lost In Translation ◽  
Synaptic Weighting

AbstractBACKGROUNDThe orbitofrontal cortex-ventromedial striatum (OFC-VMS) circuitry is widely believed to drive compulsive behavior. Hyperactivating this pathway in inbred mice produces excessive and persistent self-grooming, which has been considered a model for human compulsivity. We aimed to replicate these findings in outbred rats, where there are few reliable compulsivity models.METHODS27 male Long-Evans rats implanted with optical-fibers into VMS and with opsins delivered into OFC received optical stimulation at parameters that produce OFC-VMS plasticity and compulsive grooming in mice. We then evaluated rats for compulsive self-grooming at six timepoints: before, during, immediately after and one hour after each stimulation, one and two weeks after the ending of a 6-day stimulation protocol. To further test for effects of OFC-VMS hyperstimulation, we ran animals in three standard compulsivity assays: marble burying, nestlet shredding, and operant attentional setshifting.RESULTSOFC-VMS stimulation did not increase self-grooming or induce significant changes in nestlet shredding, marble burying, or set-shifting in rats. Follow-on evoked potential studies verified that the mouse protocol did alter OFC-VMS synaptic weighting.CONCLUSIONSIn sum, although physiological changes were observed in the OFC-VMS circuitry, we could not reproduce in a strongly powered study in rats a model of compulsive behavior previously reported in mice. If optogenetic effects on behavior do not reliably transfer between rodent species, this may have important implications for designing rodent-to-human translational pipelines.

scholarly journals BDNF haploinsufficiency induces behavioral endophenotypes of schizophrenia in male mice that are rescued by enriched environment

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mahmoud Harb ◽  
Justina Jagusch ◽  
Archana Durairaja ◽  
Thomas Endres ◽  
Volkmar Leßmann ◽  
...  
Keyword(s):  
Prepulse Inhibition ◽  
Sensorimotor Gating ◽  
Enriched Environment ◽  
Fear Learning ◽  
Set Shifting ◽  
Wild Type ◽  
Mature Adult ◽  
Attentional Set ◽  
Attentional Set Shifting ◽  
The Brain

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

scholarly journals Automatic Intra-/Extra-Dimensional Attentional Set-Shifting Task in Adolescent Mice

2021 ◽  
Vol 15 ◽  
Author(s):  
Mariasole Ciampoli ◽  
Diego Scheggia ◽  
Francesco Papaleo
Keyword(s):  
Executive Functions ◽  
Neuropsychological Test ◽  
Wisconsin Card Sorting Test ◽  
Set Shifting ◽  
Card Sorting ◽  
Attentional Set ◽  
Attentional Set Shifting ◽  
Wisconsin Card Sorting ◽  
Sorting Test ◽  
Set Shifting Task

Adolescence is a developmental period crucial for the maturation of higher-order cognitive functions. Indeed, adolescence deficits in executive functions are strong predictors of increased vulnerability to several mental disabilities later in life. Here, we tested adolescent mice in a fully-automated attentional set-shifting task equivalent to the humans’ Wisconsin Card Sorting Test (WCST) and the Cambridge Neuropsychological Test Automated Battery Intra-/Extra-Dimensional set-shift task (ID/ED). Compared to an adult, adolescent mice required more time to complete the task (≈16 days), and a higher percentage failed to finish the entire task. Nevertheless, adolescent mice completing this demanding task showed an increased effort in solving the extradimensional shift stage (EDS) compared to previous stages. Moreover, we found that this paradigm can be used to detect early cognitive dysfunctions in adolescent genetically modified mice. Thus, this automatic paradigm provides a further tool to assess attentional control in adolescent mice, and the development of dysfunctional executive functions from adolescence to adulthood.

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