Biology subjects

Harony-Nicolas, H.

Publications and source records attributed to Harony-Nicolas, H..

6 recordsLinked to original sources

bioRxiv2023

Altered neural activity in the mesoaccumbens pathway underlies impaired social reward processing in Shank3-deficient rats

Social behaviors are crucial for human connection and belonging, often impacted in conditions like Autism Spectrum Disorder (ASD). The mesoaccumbens pathway (VTA and NAc) plays a pivotal role in social behavior and is implicated in ASD. However, the impact of ASD-related mutations on social reward processing remains insufficiently explored. This study focuses on the Shank3 mutation, associated with a rare genetic condition and linked to ASD, examining its influence on the mesoaccumbens pathway during behavior, using the Shank3-deficient rat model. Our findings indicate that Shank3-deficient rats exhibit atypical social interactions and have difficulty adjusting behavior based on reward values, associated with modified neuronal activity of VTA dopaminergic and GABAergic neurons and reduced dopamine release in the NAc. Moreover, we demonstrate that manipulating VTA neuronal activity can normalize this behavior, providing insights into the effects of Shank3 mutations on social reward and behavior, and identify a potential neural pathway for intervention.

neuroscience↗

bioRxiv2023

Social Interaction Elicits Activity in Glutamatergic Neurons in the Posterior Intralaminar Complex of the Thalamus

BackgroundThe posterior intralaminar (PIL) complex of the thalamus is a multimodal nucleus that has been implicated in maternal behaviors and conspecific social behaviors in male and female rodents. Glutamatergic neurons are a major component of the PIL; however, their specific activity and role during social interactions has not yet been assessed. MethodsWe used immunohistochemistry for the immediate early gene c-fos as a proxy for neuronal activity in the PIL of mice exposed to a novel social stimulus, a novel object stimulus, or no stimulus. We then used fiber photometry to record neural activity of glutamatergic neurons in the PIL in real-time during social and non-social interactions. Finally, we used inhibitory DREADDs in glutamatergic PIL neurons and tested social preference and social habituation-dishabituation. ResultsWe observed significantly more c-fos-positive cells in the PIL of mice exposed to social versus object or no stimuli. Neural activity of PIL glutamatergic neurons was increased when male and female mice were engaged in social interaction with a same-sex juvenile or opposite-sex adult, but not a toy mouse. Neural activity positively correlated with social investigation bout length and negatively correlated with chronological order of bouts. Social preference was unaffected by inhibition; however, inhibiting activity of glutamatergic neurons in the PIL delayed the time it took female mice to form social habituation. ConclusionsTogether these findings suggest that glutamatergic PIL neurons respond to social stimuli in both male and female mice and may regulate perceptual encoding of social information to facilitate recognition of social stimuli.

neuroscience↗

bioRxiv2022

Oxytocin activity in the Paraventricular and Supramammillary Nuclei of the Hypothalamus is Essential for Social Recognition Memory in Rats

Oxytocin plays an important role in modulating social recognition memory. However, the direct implication of oxytocin neurons of the paraventricular nucleus of the hypothalamus (PVH) and their downstream hypothalamic targets in regulating short- and long-term forms of social recognition memory has not been fully investigated. In this study, we employed a chemogenetic approach to target the activity of PVH oxytocin neurons in male rats and found that specific silencing of this neuronal population led to an impairment in short- and long-term social recognition memory. We combined viral mediated fluorescent labeling of oxytocin neurons with immunohistochemical techniques and identified the supramammillary nucleus (SuM) of the hypothalamus as a target of PVH oxytocinergic axonal projections in rats. We used multiplex fluorescence in-situ hybridization to label oxytocin receptors in the SuM and determined that they are predominantly expressed in glutamatergic neurons, including those that project to the CA2 region of the hippocampus. Finally, we used a highly selective oxytocin receptor antagonist in the SuM to examine the involvement of oxytocin signaling in modulating short- and long-term social recognition memory and found that it is necessary for the formation of both. This study discovered a previously undescribed role for the SuM in regulating social recognition memory via oxytocin signaling and reinforced the specific role of PVH oxytocin neurons in regulating this form of memory.

neuroscience↗

bioRxiv2019

Reduced axonal caliber and white matter changes in a rat model of Fragile X syndrome with a deletion of a K Homology domain of Fmr1.

Fragile X syndrome (FXS) is a neurodevelopmental disorder that is caused by mutations in the FMR1 gene that are known to cause neuroanatomical alterations. The morphological underpinnings of these alterations have not been elucidated. Furthermore, while alterations have been identified in both male and female individuals, neuroanatomy in female rodent models has not been assessed. We identified structural differences in regions that are also altered in FXS in male and female rat models, including the splenium of the corpus callosum. Interestingly, different sets of regions were disrupted in male and female rat models and, remarkably, male rats had higher brain-wide diffusion than female rats overall. We found reduced axonal caliber in the splenium, offering a mechanism for its structural changes. Our results provide insight into which brain regions are vulnerable to a loss of Fmr1 expression and suggest a potential mechanism for how its loss causes white matter dysfunction in FXS.

neuroscience↗

bioRxiv2019

TrackUSF, a novel methodology for automated analysis of ultrasonic vocalizations, reveals modified social communication in a rat model of autism

Rodents emit various social ultrasonic vocalizations (USVs), which reflect their emotional state and mediate social interaction. USVs are usually analyzed by manual or semi-automated methodologies categorizing discrete USVs according to their structure in the frequency-time domains. This laborious analysis hinders effective use of USVs for screening animal models of human pathologies associated with modified social behavior, such as autism spectrum disorder (ASD). Here we present a novel, automated methodology for analyzing USVs, termed TrackUSF. To validate TrackUSF, we analyzed a dataset of mouse mating calls and compared the results with a manual analysis by a trained observer. We found that TrackUSF was capable of detecting most USVs, with less than 1% of false-positive detections. We then employed TrackUSF to social vocalizations in Shank3-deficient rats, a rat model of ASD and found, for the first time, that these vocalizations exhibit a spectrum of deviations from pro-social calls towards aggressive calls.

animal behavior and cognition↗

bioRxiv2018

Disruption of the KH1 domain of Fmr1 leads to transcriptional alterations and attentional deficits in rats

Fragile X Syndrome (FXS) is a neurodevelopmental disorder caused by mutations in the FMR1 gene. FXS is a leading monogenic cause of autism spectrum disorder (ASD) and inherited intellectual disability (ID). In most cases, the mutation is an expansion of a microsatellite (CGG triplet), which leads to suppressed expression of the fragile X mental retardation protein (FMRP), an RNA-binding protein involved in multiple aspects of mRNA metabolism. Interestingly, we found that the previously published Fmr1 knockout rat model of FXS expresses a transcript with an in-frame deletion of a K-homology (KH) domain, KH1. KH domains are RNA-binding domains of FMR1 and several of the few, known point mutations associated with FXS are found within them. We observed that this deletion leads to medial prefrontal cortex (mPFC)-dependent attention deficits, similar to those observed in FXS, and to alterations in transcriptional profiles within the mPFC, which mapped to two weighted gene coexpression network analysis modules. We demonstrated that these modules are conserved in human frontal cortex, are enriched for known FMRP targets and for genes involved in neuronal and synaptic processes, and that one is enriched for genes that are implicated in ASD, ID, and schizophrenia. Hub genes in these conserved modules represent potential targets for FXS. These findings provide support for a prefrontal deficit in FXS, indicate that attentional testing might be a reliable cross-species tool for investigating the pathophysiology of FXS and a potential readout for pharmacotherapy testing, and identify dysregulated gene expression modules in a relevant brain region.\n\nSignificance StatementThe significance of the current study lies in two key domains. First, this study demonstrates that deletion of the Fmrp-KH1 domain is sufficient to cause major mPFC-dependent attention deficits in both males and females, like those observed in both individuals with FXS and in knockout mouse models for FXS. Second, the study shows that deletion of the KH1 domain leads to alterations in the transcriptional profiles within the medial prefrontal cortex (mPFC), which are of potential translational value for subjects with FXS. These findings indicate that attentional testing might be a reliable cross-species tool for investigating the pathophysiology of FXS and a potential readout for pharmacotherapy testing and also highlight hub genes for follow up.

neuroscience↗