Biology subjects

Timofeev, I.

Publications and source records attributed to Timofeev, I..

4 recordsLinked to original sources

bioRxiv2023

The reuniens nucleus of the thalamus facilitates hippocampo-cortical dialogue during sleep

Memory consolidation during sleep depends on the interregional coupling of slow waves, spindles, and sharp wave-ripples (SWRs), across the cortex, thalamus, and hippocampus. The reuniens nucleus of the thalamus, linking the medial prefrontal cortex (mPFC) and the hippocampus, may facilitate interregional coupling during sleep. To test this hypothesis we used intracellular, extracellular unit and local field potential recordings in anesthetized and head restrained non-anesthetized cats as well as computational modelling. Electrical stimulation of the reuniens evoked both antidromic and orthodromic intracellular mPFC responses, consistent with bidirectional functional connectivity between mPFC, reuniens and hippocampus in anesthetized state. The major finding obtained from behaving animals is that at least during NREM sleep hippocampo-reuniens-mPFC form a functional loop. SWRs facilitate the triggering of thalamic spindles, which later reach neocortex. In return, transition to mPFC UP states increase the probability of hippocampal SWRs and later modulate spindle amplitude. During REM sleep hippocampal theta activity provides periodic locking of reuniens neuronal firing and strong crosscorrelation at LFP level, but the values of reuniens-mPFC crosscorrelation was relatively low and theta power at mPFC was low. The neural mass model of this network demonstrates that the strength of bidirectional hippocampo-thalamic connections determines the coupling of oscillations, suggesting a mechanistic link between synaptic weights and the propensity for interregional synchrony. Our results demonstrate the presence of functional connectivity in hippocampo-thalamo-cortical network, but the efficacy of this connectivity is modulated by behavioral state. Impact StatementThe nucleus reuniens of the thalamus play a central role in synchronizing the mPFC-hippocampal network during sleep and integrates converging activity from hippocampal and mPFC oscillations.

neuroscience↗

bioRxiv2020

Chronic stress induces sex-specific functional and morphological alterations in cortico-accumbal and cortico-tegmental pathways.

BackgroundThe medial prefrontal cortex (mPFC) is part of a complex circuit controlling stress responses by sending projections to different limbic structures including the nucleus accumbens (NAc) and ventral tegmental area (VTA). However, the impact of chronic stress on NAc- and VTA-projecting mPFC neurons is still unknown and the distinct contribution of these pathways to stress responses in males and females is unclear. MethodsBehavioral stress responses were induced by 21 days of chronic variable stress (CVS) in male and female C57BL6 mice. An inter-sectional viral approach was used to label both pathways and assess the functional, morphological, and transcriptional adaptations in NAc- and VTA-projecting mPFC neurons in stressed males and females. Using chemogenetic approaches, we modified neuronal activity of NAc-projecting mPFC neurons to decipher their contribution to stress phenotypes. ResultsCVS induced depressive-like behaviors in males and females. NAc- and VTA-projecting mPFC neurons exhibited sex-specific functional, morphological, and transcriptional alterations. The functional changes were more severe in females in NAc-projecting mPFC neurons while males exhibited more drastic reductions in dendritic complexity in VTA-projecting mPFC neurons after CVS. Finally, chemogenetic overactivation of the cortico-accumbal pathway triggered anxiety and behavioral despair in both sexes while its inhibition rescued the phenotype only in females. ConclusionsOur results suggest that by changing the activity of transcriptional programs controlling neuronal plasticity, CVS interferes with the morphological and synaptic properties of the cortico-accumbal and tegmental pathways differently in males and females contributing to the expression of anxiety and depressive-like behaviors distinctly in a sex-specific fashion.

neuroscience↗

bioRxiv2019

A map of transcriptional heterogeneity and regulatory variation in human microglia

Microglia, the tissue resident macrophages of the CNS, are implicated in a broad range of neurological pathologies, from acute brain injury to dementia. Here, we profiled gene expression variation in primary human microglia isolated from 141 patients undergoing neurosurgery. Using single cell and bulk RNA sequencing, we defined distinct cellular populations of acutely in vivo-activated microglia, and characterised a dramatic switch in microglial population composition in patients suffering from acute brain injury. We mapped expression quantitative trait loci (eQTLs) in human microglia and show that many disease-associated eQTLs in microglia replicate well in a human induced pluripotent stem cell (hIPSC) derived macrophage model system. Using ATAC-seq from 95 individuals in this hIPSC model we fine-map candidate causal variants at risk loci for Alzheimers disease, the most prevalent neurodegenerative condition in acute brain injury patients. Our study provides the first population-scale transcriptional map of a critically important cell for neurodegenerative disorders.

genomics↗

bioRxiv2019

Differential expression of deltaFosB in reward processing regions between binge eating prone and resistant female rats

Binge eating disorder (BED) is characterized by bingeing and compulsivity. Even though BED is the most prevalent eating disorder, little is known about its pathophysiology. We aimed to identify brain regions and neuron subtypes implicated in the development of binge-like eating in a female rat model. We separated rats into binge eating prone (BEP) and binge eating resistant (BER) phenotypes based on the amount of sucrose they consumed following foot-shock stress. We quantified deltaFosB ({Delta}FosB) expression to assess chronic neuronal activation during phenotyping. The number of {Delta}FosB-expressing neurons was: 1) higher in BEP than BER rats in reward processing areas (medial prefrontal cortex (mPFC), nucleus accumbens (Acb), and ventral tegmental area (VTA)); 2) similar in taste processing areas (insular cortex and parabrachial nucleus); 3) higher in the paraventricular nucleus of BEP than BER rats, but not different in the locus coeruleus, which are stress processing structures. To study subtypes of {Delta}FosB-expressing neurons in the reward system, we performed in situ hybridization for glutamate decarboxylase 65 and tyrosine hydroxylase mRNA after {Delta}FosB immunohistochemistry. In the mPFC and Acb, the proportions of gamma-aminobutyric acidergic (GABAergic) and non-GABAergic {Delta}FosB-expressing neurons were similar in BER and BEP rats. In the VTA, while the proportion of dopaminergic {Delta}FosB-expressing neurons was similar in both phenotypes, the proportion of GABAergic {Delta}FosB-expressing neurons was higher in BER than BEP rats. Our results suggest that reward processing brain regions, particularly the VTA, are important for the development of binge-like eating.\n\nSignificanceBecause {Delta}FosB expression is associated with a reduction of activity in neurons, a higher expression of {Delta}FosB in the mPFC, Acb, and VTA of binge eating prone rats compared to binge eating resistant rats suggests a decrease in neuronal activity in these regions, which is consistent with results observed in neuroimaging studies in binge eating disorder patients. This decrease in activity due to {Delta}FosB expression may underlie the compulsivity and overconsumption of palatable food observed in both our rat model of binge-like eating and binge eating disorder patients.

neuroscience↗