Biology subjects

Kros, L.

Publications and source records attributed to Kros, L..

3 recordsLinked to original sources

bioRxiv2023

The modified elevated gap interaction test: A novel paradigm to assess social preference.

Social deficits play a role in numerous psychiatric, neurological and neurodevelopmental disorders. Relating complex behavior, such as social interaction, to brain activity remains one of the biggest goals and challenges in neuroscience. Availability of standardized behavioral tests that assess social preference is however, limited. Here, we present a novel behavioral set-up and paradigm that we developed to measure social behavior, the modified elevated gap interaction test (MEGIT). In this test, animals are placed on one of two elevated platforms separated by a gap, in which they can engage in whisker-interaction with either a conspecific or an object. This allows quantification of social preference in real interaction rather than just proximity and forms an ideal setup for social behavior-related neuronal recordings. We provide a detailed description of the paradigm and its highly reliable, deep-learning based analysis, and show test results obtained from wild-type animals as well as genetic mouse models for disorders characterized by either hyposocial (autism spectrum disorder; ASD) or hypersocial (Williams Beuren syndrome; WBS) behavior. Wild-type animals show a clear preference for whisker interaction with another mouse rather than an inanimate object. This preference proved to be significantly smaller in mice carrying a mutation that can cause ASD in humans, whereas it is larger in WBS murine models. Differences in social preference became even more pronounced when corrected for hyperactive or repetitive behavior. The results indicate that MEGIT is a sensitive and reliable test for detecting and investigating social phenotypes.

neuroscience↗

bioRxiv2023

Vascular abnormalities in heart and brain are associated with cardiovascular and neurological symptoms in a novel mouse model for Williams syndrome

Williams syndrome is a developmental disorder caused by a microdeletion entailing the loss of a single copy of 25-27 genes on chromosome 7q11.23. Patients suffer from cardiovascular and neuropsychological symptoms. Structural abnormalities of the cardiovascular system in Williams syndrome have been attributed to the hemizygous loss of the elastin (ELN) gene. In contrast, the neuropsychological consequences of Williams syndrome, including sensorimotor deficits, hypersociability and cognitive impairments, have been mainly attributed to altered expression of transcription factors like LIMK1, GTF2I and GTF2IRD1, while the potential impact of altered cerebrovascular function has been largely overlooked. To study the relationship between Williams syndrome mutations and vascularization of both the heart and brain, we generated a mouse model carrying a relatively long microdeletion (LD) that includes the Ncf1 gene, thereby minimizing the confounding impact of hypertension. LD mice had elongated and tortuous aortas but, unlike Eln haploinsufficient mice, showed no signs of structural cardiac hypertrophy. Remarkably, LD mice also displayed structural abnormalities in coronary and brain vessels, including disorganized extracellular matrices. Importantly, LD mice faithfully replicated both cardiovascular and neuropsychological symptoms observed in patients. The phenotype was even more comprehensive than former models, with structure-function correlations evident in aberrant auditory and motor behaviors resembling those in patients with Williams syndrome. Together, our findings suggest that not only cardiovascular but also neuropsychological symptoms in Williams syndrome may be driven in part by vascular abnormalities affecting both heart and brain. Significance StatementWilliams syndrome is caused by microdeletion of 25-27 genes on chromosome 7q11.23, resulting in cardiovascular and neuropsychological symptoms. It remains unclear how the affected genes interact and whether cardiovascular deficits influence brain function. We developed and characterized a mouse model with the longest Williams syndrome microdeletion to date. This model reveals interactions between genes that can be compensatory or additive: haploinsufficiency of Ncf1 may counteract the cardiac hypertrophy caused by Eln deletion, while vascular defects that are potentially due to Eln haploinsufficiency extend to the brain and may worsen neuropsychological symptoms. Our findings support the hypothesis that structural vascular deficits putatively contribute to both cardiac and cognitive phenotypes in Williams syndrome, opening new avenues for understanding and treating this syndrome.

systems biology↗

bioRxiv2020

Cerebellar Purkinje cells can differentially modulate coherence between sensory and motor cortex depending on region and behavior

Coherence among sensory and motor cortices is indicative of binding of critical functions in perception, motor planning, action and sleep. Evidence is emerging that the cerebellum can impose coherence between cortical areas, but how and when it does so is unclear. Here, we studied coherence between primary somatosensory (S1) and motor (M1) cortices during sensory stimulation of the whiskers in the presence and absence of optogenetic stimulation of cerebellar Purkinje cells in awake mice. Purkinje cell activation enhanced and reduced sensory-induced S1-M1 coherence in the theta and gamma bands, respectively. This impact only occurred when Purkinje cell stimulation was given simultaneously with sensory stimulation; a 20 ms delay was sufficient to alleviate its impact, suggesting the existence of a fast, cerebellar sensory pathway to S1 and M1. The suppression of gamma band coherence upon Purkinje cell stimulation was significantly stronger during trials with relatively large whisker movements, whereas the theta band changes did not show this correlation. In line with the anatomical distribution of the simple spike and complex spike responses to whisker stimulation, this suppression also occurred following focal stimulation of medial crus 2, but not of lateral crus 1. Granger causality analyses and computational modeling of the involved networks suggest that Purkinje cells control S1-M1 coherence most prominently via the ventrolateral thalamus and M1. Our results indicate that coherences between sensory and motor cortices in different frequency ranges can be dynamically modulated by cerebellar input, and that the modulation depends on the behavioral context and is site-specific. Significance StatementCoherent activity between sensory and motor areas is essential in sensorimotor integration. We show here that the cerebellum can differentially affect cortical theta and gamma band coherences evoked by whisker stimulation via a fast ascending and predictive pathway. In line with the functional heterogeneity of its modular organization, the impact of the cerebellum is region-specific and tuned to ongoing motor responses. These data highlight site-specific and context-dependent interactions between the cerebellum and the cerebral cortex that can come into play during a plethora of sensorimotor functions.

neuroscience↗